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==CRYSTAL STRUCTURE OF PHOSPHORYLATED RET TYROSINE KINASE DOMAIN COMPLEXED WITH THE INHIBITOR ZD6474==
 
<StructureSection load='2ivu' size='340' side='right' caption='[[2ivu]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
==Crystal structure of phosphorylated RET tyrosine kinase domain complexed with the inhibitor ZD6474==
<StructureSection load='2ivu' size='340' side='right'caption='[[2ivu]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[2ivu]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IVU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2IVU FirstGlance]. <br>
<table><tr><td colspan='2'>[[2ivu]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IVU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IVU FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=ZD6:4-BROMO-2-FLUORO-N-[(4E)-6-METHOXY-7-[(1-METHYLPIPERIDIN-4-YL)METHOXY]QUINAZOLIN-4(1H)-YLIDENE]ANILINE'>ZD6</scene><br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=ZD6:4-BROMO-2-FLUORO-N-[(4E)-6-METHOXY-7-[(1-METHYLPIPERIDIN-4-YL)METHOXY]QUINAZOLIN-4(1H)-YLIDENE]ANILINE'>ZD6</scene></td></tr>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1xpd|1xpd]], [[2ivs|2ivs]], [[2ivt|2ivt]], [[2ivv|2ivv]]</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ivu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ivu OCA], [https://pdbe.org/2ivu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ivu RCSB], [https://www.ebi.ac.uk/pdbsum/2ivu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ivu ProSAT]</span></td></tr>
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
</table>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ivu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ivu OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2ivu RCSB], [http://www.ebi.ac.uk/pdbsum/2ivu PDBsum]</span></td></tr>
== Disease ==
<table>
[https://www.uniprot.org/uniprot/RET_HUMAN RET_HUMAN] Unilateral renal dysplasia;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia type 2B;Multiple endocrine neoplasia type 2A;Hirschsprung disease;Bilateral renal agenesis;Bilateral renal dysplasia;Ondine syndrome;Papillary or follicular thyroid carcinoma. Colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The disease may be caused by mutations affecting the gene represented in this entry.  Hirschsprung disease 1 (HSCR1) [MIM:[https://omim.org/entry/142623 142623]: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:7704557</ref> <ref>PMID:7881414</ref> <ref>PMID:8114938</ref> <ref>PMID:8114939</ref> <ref>PMID:7633441</ref> <ref>PMID:7581377</ref> <ref>PMID:8595427</ref> <ref>PMID:9043870</ref> <ref>PMID:9090527</ref> <ref>PMID:9259198</ref> <ref>PMID:9094028</ref> <ref>PMID:9384613</ref> <ref>PMID:10090908</ref> <ref>PMID:10484767</ref> <ref>PMID:10618407</ref> <ref>PMID:22174939</ref>   Medullary thyroid carcinoma (MTC) [MIM:[https://omim.org/entry/155240 155240]: Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:7881414</ref> <ref>PMID:9259198</ref> <ref>PMID:7849720</ref> <ref>PMID:7874109</ref> <ref>PMID:8625130</ref> <ref>PMID:7845675</ref> <ref>PMID:7784092</ref> <ref>PMID:8557249</ref> <ref>PMID:8807338</ref> <ref>PMID:9398735</ref> <ref>PMID:9223675</ref> <ref>PMID:9677065</ref> <ref>PMID:9452077</ref> <ref>PMID:9506724</ref> <ref>PMID:9621513</ref> <ref>PMID:10323403</ref> <ref>PMID:10826520</ref> <ref>PMID:11692159</ref>   Multiple neoplasia 2B (MEN2B) [MIM:[https://omim.org/entry/162300 162300]: Uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophtalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:8625130</ref> <ref>PMID:8807338</ref> <ref>PMID:9223675</ref> <ref>PMID:7911697</ref> <ref>PMID:7906866</ref> <ref>PMID:7906417</ref> <ref>PMID:8595427</ref> <ref>PMID:9360560</ref> <ref>PMID:9294615</ref>  Pheochromocytoma (PCC) [MIM:[https://omim.org/entry/171300 171300]: A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Multiple neoplasia 2A (MEN2A) [MIM:[https://omim.org/entry/171400 171400]: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:7881414</ref> <ref>PMID:9384613</ref> <ref>PMID:7874109</ref> <ref>PMID:8625130</ref> <ref>PMID:8807338</ref> <ref>PMID:9223675</ref> <ref>PMID:9621513</ref> <ref>PMID:8103403</ref> <ref>PMID:8099202</ref> <ref>PMID:7915165</ref> <ref>PMID:7860065</ref> <ref>PMID:8626834</ref> <ref>PMID:9097963</ref> <ref>PMID:9452064</ref> <ref>PMID:10522989</ref>   Thyroid papillary carcinoma (TPC) [MIM:[https://omim.org/entry/188550 188550]: A common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving RET have been found in thyroid papillary carcinomas. Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene; inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene; translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene; translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion; translocation t(6;10)(p21.3;q11.2) with RFP generates the Delta RFP/RET oncogene; translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene; translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene. The PTC5 oncogene has been found in 2 cases of PACT in children exposed to radioactive fallout after Chernobyl. A chromosomal aberration involving TRIM27/RFP is found in thyroid papillary carcinomas. Translocation t(6;10)(p21.3;q11.2) with RET. The translocation generates TRIM27/RET and delta TRIM27/RET oncogenes.  Renal adysplasia (RADYS) [MIM:[https://omim.org/entry/191830 191830]: Renal agenesis refers to the absence of one (unilateral) or both (bilateral) kidneys at birth. Bilateral renal agenesis belongs to a group of perinatally lethal renal diseases, including severe bilateral renal dysplasia, unilateral renal agenesis with contralateral dysplasia and severe obstructive uropathy. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:18252215</ref>  Congenital central hypoventilation syndrome (CCHS) [MIM:[https://omim.org/entry/209880 209880]: Rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:9497256</ref> <ref>PMID:12086152</ref> <ref>PMID:14566559</ref>
== Function ==
[https://www.uniprot.org/uniprot/RET_HUMAN RET_HUMAN] Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration.<ref>PMID:20064382</ref> <ref>PMID:20616503</ref> <ref>PMID:20702524</ref> <ref>PMID:21357690</ref> <ref>PMID:21454698</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/iv/2ivu_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/iv/2ivu_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ivu ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
Line 27: Line 30:
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 2ivu" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
Line 32: Line 36:
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Large Structures]]
[[Category: Knowles, P P.]]
[[Category: Knowles PP]]
[[Category: Mcdonald, N Q.]]
[[Category: McDonald NQ]]
[[Category: Murray-Rust, J.]]
[[Category: Murray-Rust J]]
[[Category: Atp-binding]]
[[Category: Chromosomal translocation]]
[[Category: Disease mutation]]
[[Category: Gdnf receptor]]
[[Category: Hirschsprung disease]]
[[Category: Kinase]]
[[Category: Membrane]]
[[Category: Nucleotide-binding]]
[[Category: Phosphorylation]]
[[Category: Phosphotransferase]]
[[Category: Proto-oncogene]]
[[Category: Ret]]
[[Category: Transferase]]
[[Category: Transmembrane]]
[[Category: Tyrosine kinase]]
[[Category: Tyrosine-protein kinase]]

Latest revision as of 12:12, 6 November 2024

Crystal structure of phosphorylated RET tyrosine kinase domain complexed with the inhibitor ZD6474Crystal structure of phosphorylated RET tyrosine kinase domain complexed with the inhibitor ZD6474

Structural highlights

2ivu is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.5Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

RET_HUMAN Unilateral renal dysplasia;Familial medullary thyroid carcinoma;Multiple endocrine neoplasia type 2B;Multiple endocrine neoplasia type 2A;Hirschsprung disease;Bilateral renal agenesis;Bilateral renal dysplasia;Ondine syndrome;Papillary or follicular thyroid carcinoma. Colorectal cancer (CRC) [MIM:114500: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The disease may be caused by mutations affecting the gene represented in this entry. Hirschsprung disease 1 (HSCR1) [MIM:142623: A disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] Medullary thyroid carcinoma (MTC) [MIM:155240: Rare tumor derived from the C cells of the thyroid. Three hereditary forms are known, that are transmitted in an autosomal dominant fashion: (a) multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC cases and where MTC is the only clinical manifestation. Note=The disease is caused by mutations affecting the gene represented in this entry.[17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] Multiple neoplasia 2B (MEN2B) [MIM:162300: Uncommon inherited cancer syndrome characterized by predisposition to MTC and phaeochromocytoma which is associated with marfanoid habitus, mucosal neuromas, skeletal and ophtalmic abnormalities, and ganglioneuromas of the intestine tract. Then the disease progresses rapidly with the development of metastatic MTC and a pheochromocytome in 50% of cases. Note=The disease is caused by mutations affecting the gene represented in this entry.[35] [36] [37] [38] [39] [40] [41] [42] [43] Pheochromocytoma (PCC) [MIM:171300: A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Multiple neoplasia 2A (MEN2A) [MIM:171400: The most frequent form of medullary thyroid cancer (MTC). It is an inherited cancer syndrome characterized by MTC, phaeochromocytoma and/or hyperparathyroidism. Note=The disease is caused by mutations affecting the gene represented in this entry.[44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] Thyroid papillary carcinoma (TPC) [MIM:188550: A common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving RET have been found in thyroid papillary carcinomas. Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene; inversion inv(10)(q11.2;q11.2) generates the RET/NCOA4 (PTC3) oncogene; translocation t(10;14)(q11;q32) with GOLGA5 generates the RET/GOLGA5 (PTC5) oncogene; translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET fusion; translocation t(6;10)(p21.3;q11.2) with RFP generates the Delta RFP/RET oncogene; translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET (PTC7) oncogene; translocation t(7;10)(q32;q11) with TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene. The PTC5 oncogene has been found in 2 cases of PACT in children exposed to radioactive fallout after Chernobyl. A chromosomal aberration involving TRIM27/RFP is found in thyroid papillary carcinomas. Translocation t(6;10)(p21.3;q11.2) with RET. The translocation generates TRIM27/RET and delta TRIM27/RET oncogenes. Renal adysplasia (RADYS) [MIM:191830: Renal agenesis refers to the absence of one (unilateral) or both (bilateral) kidneys at birth. Bilateral renal agenesis belongs to a group of perinatally lethal renal diseases, including severe bilateral renal dysplasia, unilateral renal agenesis with contralateral dysplasia and severe obstructive uropathy. Note=The disease is caused by mutations affecting the gene represented in this entry.[59] Congenital central hypoventilation syndrome (CCHS) [MIM:209880: Rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. Note=The disease is caused by mutations affecting the gene represented in this entry.[60] [61] [62]

Function

RET_HUMAN Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration.[63] [64] [65] [66] [67]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The RET proto-oncogene encodes a receptor tyrosine kinase for the glial cell line-derived neurotrophic factor family of ligands. Loss-of-function mutations in RET are implicated in Hirschsprung disease, whereas activating mutations in RET are found in human cancers, including familial medullar thyroid carcinoma and multiple endocrine neoplasias 2A and 2B. We report here the biochemical characterization of the human RET tyrosine kinase domain and the structure determination of the non-phosphorylated and phosphorylated forms. Both structures adopt the same active kinase conformation competent to bind ATP and substrate and have a pre-organized activation loop conformation that is independent of phosphorylation status. In agreement with the structural data, enzyme kinetic data show that autophosphorylation produces only a modest increase in activity. Longer forms of RET containing the juxtamembrane domain and C-terminal tail exhibited similar kinetic behavior, implying that there is no cis-inhibitory mechanism within the RET intracellular domain. Our results suggest the existence of alternative inhibitory mechanisms, possibly in trans, for the autoregulation of RET kinase activity. We also present the structures of the RET tyrosine kinase domain bound to two inhibitors, the pyrazolopyrimidine PP1 and the clinically relevant 4-anilinoquinazoline ZD6474. These structures explain why certain multiple endocrine neoplasia 2-associated RET mutants found in patients are resistant to inhibition and form the basis for design of more effective inhibitors.

Structure and chemical inhibition of the RET tyrosine kinase domain.,Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, Ibanez CF, McDonald NQ J Biol Chem. 2006 Nov 3;281(44):33577-87. Epub 2006 Aug 23. PMID:16928683[68]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Yin L, Barone V, Seri M, Bolino A, Bocciardi R, Ceccherini I, Pasini B, Tocco T, Lerone M, Cywes S, et al.. Heterogeneity and low detection rate of RET mutations in Hirschsprung disease. Eur J Hum Genet. 1994;2(4):272-80. PMID:7704557
  2. ↑ Mulligan LM, Eng C, Attie T, Lyonnet S, Marsh DJ, Hyland VJ, Robinson BG, Frilling A, Verellen-Dumoulin C, Safar A, et al.. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet. 1994 Dec;3(12):2163-7. PMID:7881414
  3. ↑ Romeo G, Ronchetto P, Luo Y, Barone V, Seri M, Ceccherini I, Pasini B, Bocciardi R, Lerone M, Kaariainen H, et al.. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature. 1994 Jan 27;367(6461):377-8. PMID:8114938 doi:http://dx.doi.org/10.1038/367377a0
  4. ↑ Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fekete C, Ponder BA, Munnich A. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature. 1994 Jan 27;367(6461):378-80. PMID:8114939 doi:http://dx.doi.org/10.1038/367378a0
  5. ↑ Angrist M, Bolk S, Thiel B, Puffenberger EG, Hofstra RM, Buys CH, Cass DT, Chakravarti A. Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum Mol Genet. 1995 May;4(5):821-30. PMID:7633441
  6. ↑ Attie T, Pelet A, Edery P, Eng C, Mulligan LM, Amiel J, Boutrand L, Beldjord C, Nihoul-Fekete C, Munnich A, et al.. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet. 1995 Aug;4(8):1381-6. PMID:7581377
  7. ↑ Kitamura Y, Scavarda N, Wells SA Jr, Jackson CE, Goodfellow PJ. Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B. Hum Mol Genet. 1995 Oct;4(10):1987-8. PMID:8595427
  8. ↑ Yin L, Seri M, Barone V, Tocco T, Scaranari M, Romeo G. Prevalence and parental origin of de novo RET mutations in Hirschsprung's disease. Eur J Hum Genet. 1996;4(6):356-8. PMID:9043870
  9. ↑ Seri M, Yin L, Barone V, Bolino A, Celli I, Bocciardi R, Pasini B, Ceccherini I, Lerone M, Kristoffersson U, Larsson LT, Casasa JM, Cass DT, Abramowicz MJ, Vanderwinden JM, Kravcenkiene I, Baric I, Silengo M, Martucciello G, Romeo G. Frequency of RET mutations in long- and short-segment Hirschsprung disease. Hum Mutat. 1997;9(3):243-9. PMID:9090527 doi:<243::AID-HUMU5>3.0.CO;2-8 10.1002/(SICI)1098-1004(1997)9:3<243::AID-HUMU5>3.0.CO;2-8
  10. ↑ Peretz H, Luboshitsky R, Baron E, Biton A, Gershoni R, Usher S, Grynberg E, Yakobson E, Graff E, Lapidot M. Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting. Hum Mutat. 1997;10(2):155-9. PMID:9259198 doi:<155::AID-HUMU7>3.0.CO;2-J 10.1002/(SICI)1098-1004(1997)10:2<155::AID-HUMU7>3.0.CO;2-J
  11. ↑ Kusafuka T, Wang Y, Puri P. Mutation analysis of the RET, the endothelin-B receptor, and the endothelin-3 genes in sporadic cases of Hirschsprung's disease. J Pediatr Surg. 1997 Mar;32(3):501-4. PMID:9094028
  12. ↑ Decker RA, Peacock ML, Watson P. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet. 1998 Jan;7(1):129-34. PMID:9384613
  13. ↑ Auricchio A, Griseri P, Carpentieri ML, Betsos N, Staiano A, Tozzi A, Priolo M, Thompson H, Bocciardi R, Romeo G, Ballabio A, Ceccherini I. Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease. Am J Hum Genet. 1999 Apr;64(4):1216-21. PMID:10090908
  14. ↑ Geneste O, Bidaud C, De Vita G, Hofstra RM, Tartare-Deckert S, Buys CH, Lenoir GM, Santoro M, Billaud M. Two distinct mutations of the RET receptor causing Hirschsprung's disease impair the binding of signalling effectors to a multifunctional docking site. Hum Mol Genet. 1999 Oct;8(11):1989-99. PMID:10484767
  15. ↑ Bolk S, Pelet A, Hofstra RM, Angrist M, Salomon R, Croaker D, Buys CH, Lyonnet S, Chakravarti A. A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):268-73. PMID:10618407
  16. ↑ So MT, Leon TY, Cheng G, Tang CS, Miao XP, Cornes BK, Diem NN, Cui L, Ngan ES, Lui VC, Wu XZ, Wang B, Wang H, Yuan ZW, Huang LM, Li L, Xia H, Zhu D, Liu J, Nguyen TL, Chan IH, Chung PH, Liu XL, Zhang R, Wong KK, Sham PC, Cherny SS, Tam PK, Garcia-Barcelo MM. RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients. PLoS One. 2011;6(12):e28986. doi: 10.1371/journal.pone.0028986. Epub 2011 Dec 9. PMID:22174939 doi:10.1371/journal.pone.0028986
  17. ↑ Mulligan LM, Eng C, Attie T, Lyonnet S, Marsh DJ, Hyland VJ, Robinson BG, Frilling A, Verellen-Dumoulin C, Safar A, et al.. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet. 1994 Dec;3(12):2163-7. PMID:7881414
  18. ↑ Peretz H, Luboshitsky R, Baron E, Biton A, Gershoni R, Usher S, Grynberg E, Yakobson E, Graff E, Lapidot M. Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting. Hum Mutat. 1997;10(2):155-9. PMID:9259198 doi:<155::AID-HUMU7>3.0.CO;2-J 10.1002/(SICI)1098-1004(1997)10:2<155::AID-HUMU7>3.0.CO;2-J
  19. ↑ Blaugrund JE, Johns MM Jr, Eby YJ, Ball DW, Baylin SB, Hruban RH, Sidransky D. RET proto-oncogene mutations in inherited and sporadic medullary thyroid cancer. Hum Mol Genet. 1994 Oct;3(10):1895-7. PMID:7849720
  20. ↑ Schuffenecker I, Billaud M, Calender A, Chambe B, Ginet N, Calmettes C, Modigliani E, Lenoir GM. RET proto-oncogene mutations in French MEN 2A and FMTC families. Hum Mol Genet. 1994 Nov;3(11):1939-43. PMID:7874109
  21. ↑ Komminoth P, Kunz EK, Matias-Guiu X, Hiort O, Christiansen G, Colomer A, Roth J, Heitz PU. Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas. Cancer. 1995 Aug 1;76(3):479-89. PMID:8625130
  22. ↑ Eng C, Smith DP, Mulligan LM, Healey CS, Zvelebil MJ, Stonehouse TJ, Ponder MA, Jackson CE, Waterfield MD, Ponder BA. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene. 1995 Feb 2;10(3):509-13. PMID:7845675
  23. ↑ Bolino A, Schuffenecker I, Luo Y, Seri M, Silengo M, Tocco T, Chabrier G, Houdent C, Murat A, Schlumberger M, et al.. RET mutations in exons 13 and 14 of FMTC patients. Oncogene. 1995 Jun 15;10(12):2415-9. PMID:7784092
  24. ↑ Landsvater RM, Jansen RP, Hofstra RM, Buys CH, Lips CJ, Ploos van Amstel HK. Mutation analysis of the RET proto-oncogene in Dutch families with MEN 2A, MEN 2B and FMTC: two novel mutations and one de novo mutation for MEN 2A. Hum Genet. 1996 Jan;97(1):11-4. PMID:8557249
  25. ↑ Kambouris M, Jackson CE, Feldman GL. Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Hum Mutat. 1996;8(1):64-70. PMID:8807338 doi:<64::AID-HUMU9>3.0.CO;2-P 10.1002/(SICI)1098-1004(1996)8:1<64::AID-HUMU9>3.0.CO;2-P
  26. ↑ Hofstra RM, Fattoruso O, Quadro L, Wu Y, Libroia A, Verga U, Colantuoni V, Buys CH. A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab. 1997 Dec;82(12):4176-8. PMID:9398735
  27. ↑ Kitamura Y, Goodfellow PJ, Shimizu K, Nagahama M, Ito K, Kitagawa W, Akasu H, Takami H, Tanaka S, Wells SA Jr. Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC. Oncogene. 1997 Jun 26;14(25):3103-6. PMID:9223675 doi:10.1038/sj.onc.1201102
  28. ↑ Oriola J, Paramo C, Halperin I, Garcia-Mayor RV, Rivera-Fillat F. Novel point mutation in exon 10 of the RET proto-oncogene in a family with medullary thyroid carcinoma. Am J Med Genet. 1998 Jul 7;78(3):271-3. PMID:9677065
  29. ↑ Fattoruso O, Quadro L, Libroia A, Verga U, Lupoli G, Cascone E, Colantuoni V. A GTG to ATG novel point mutation at codon 804 in exon 14 of the RET proto-oncogene in two families affected by familial medullary thyroid carcinoma. Hum Mutat. 1998;Suppl 1:S167-71. PMID:9452077
  30. ↑ Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussendorf M, Raue F, Ritter MM, Hoppner W. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab. 1998 Mar;83(3):770-4. PMID:9506724
  31. ↑ Shirahama S, Ogura K, Takami H, Ito K, Tohsen T, Miyauchi A, Nakamura Y. Mutational analysis of the RET proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma. J Hum Genet. 1998;43(2):101-6. PMID:9621513 doi:10.1007/s100380050048
  32. ↑ Pigny P, Bauters C, Wemeau JL, Houcke ML, Crepin M, Caron P, Giraud S, Calender A, Buisine MP, Kerckaert JP, Porchet N. A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma. J Clin Endocrinol Metab. 1999 May;84(5):1700-4. PMID:10323403
  33. ↑ Bartsch DK, Hasse C, Schug C, Barth P, Rothmund M, Hoppner W. A RET double mutation in the germline of a kindred with FMTC. Exp Clin Endocrinol Diabetes. 2000;108(2):128-32. PMID:10826520 doi:10.1055/s-2000-5806
  34. ↑ Kalinin VN, Amosenko FA, Shabanov MA, Lubchenko LN, Hosch SB, Garkavtseva RF, Izbicki JR. Three novel mutations in the RET proto-oncogene. J Mol Med (Berl). 2001 Oct;79(10):609-12. PMID:11692159 doi:10.1007/s001090100250
  35. ↑ Komminoth P, Kunz EK, Matias-Guiu X, Hiort O, Christiansen G, Colomer A, Roth J, Heitz PU. Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas. Cancer. 1995 Aug 1;76(3):479-89. PMID:8625130
  36. ↑ Kambouris M, Jackson CE, Feldman GL. Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Hum Mutat. 1996;8(1):64-70. PMID:8807338 doi:<64::AID-HUMU9>3.0.CO;2-P 10.1002/(SICI)1098-1004(1996)8:1<64::AID-HUMU9>3.0.CO;2-P
  37. ↑ Kitamura Y, Goodfellow PJ, Shimizu K, Nagahama M, Ito K, Kitagawa W, Akasu H, Takami H, Tanaka S, Wells SA Jr. Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC. Oncogene. 1997 Jun 26;14(25):3103-6. PMID:9223675 doi:10.1038/sj.onc.1201102
  38. ↑ Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann GF, Jackson CE, Tunnacliffe A, et al.. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994 Feb;3(2):237-41. PMID:7911697
  39. ↑ Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, Romeo G, et al.. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994 Jan 27;367(6461):375-6. PMID:7906866 doi:http://dx.doi.org/10.1038/367375a0
  40. ↑ Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, Wells SA Jr, Goodfellow PJ, Donis-Keller H. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1579-83. PMID:7906417
  41. ↑ Kitamura Y, Scavarda N, Wells SA Jr, Jackson CE, Goodfellow PJ. Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B. Hum Mol Genet. 1995 Oct;4(10):1987-8. PMID:8595427
  42. ↑ Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mulligan LM, Zajac JD, Robinson BG, Eng C. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997 Nov;82(11):3902-4. PMID:9360560
  43. ↑ Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene. 1997 Sep 4;15(10):1213-7. PMID:9294615 doi:10.1038/sj.onc.1201481
  44. ↑ Mulligan LM, Eng C, Attie T, Lyonnet S, Marsh DJ, Hyland VJ, Robinson BG, Frilling A, Verellen-Dumoulin C, Safar A, et al.. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet. 1994 Dec;3(12):2163-7. PMID:7881414
  45. ↑ Decker RA, Peacock ML, Watson P. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet. 1998 Jan;7(1):129-34. PMID:9384613
  46. ↑ Schuffenecker I, Billaud M, Calender A, Chambe B, Ginet N, Calmettes C, Modigliani E, Lenoir GM. RET proto-oncogene mutations in French MEN 2A and FMTC families. Hum Mol Genet. 1994 Nov;3(11):1939-43. PMID:7874109
  47. ↑ Komminoth P, Kunz EK, Matias-Guiu X, Hiort O, Christiansen G, Colomer A, Roth J, Heitz PU. Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas. Cancer. 1995 Aug 1;76(3):479-89. PMID:8625130
  48. ↑ Kambouris M, Jackson CE, Feldman GL. Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Hum Mutat. 1996;8(1):64-70. PMID:8807338 doi:<64::AID-HUMU9>3.0.CO;2-P 10.1002/(SICI)1098-1004(1996)8:1<64::AID-HUMU9>3.0.CO;2-P
  49. ↑ Kitamura Y, Goodfellow PJ, Shimizu K, Nagahama M, Ito K, Kitagawa W, Akasu H, Takami H, Tanaka S, Wells SA Jr. Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC. Oncogene. 1997 Jun 26;14(25):3103-6. PMID:9223675 doi:10.1038/sj.onc.1201102
  50. ↑ Shirahama S, Ogura K, Takami H, Ito K, Tohsen T, Miyauchi A, Nakamura Y. Mutational analysis of the RET proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma. J Hum Genet. 1998;43(2):101-6. PMID:9621513 doi:10.1007/s100380050048
  51. ↑ Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA Jr. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993 Jul;2(7):851-6. PMID:8103403
  52. ↑ Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, et al.. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993 Jun 3;363(6428):458-60. PMID:8099202 doi:http://dx.doi.org/10.1038/363458a0
  53. ↑ Xue F, Yu H, Maurer LH, Memoli VA, Nutile-McMenemy N, Schuster MK, Bowden DW, Mao J, Noll WW. Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. Hum Mol Genet. 1994 Apr;3(4):635-8. PMID:7915165
  54. ↑ Takiguchi-Shirahama S, Koyama K, Miyauchi A, Wakasugi T, Oishi S, Takami H, Hikiji K, Nakamura Y. Germline mutations of the RET proto-oncogene in eight Japanese patients with multiple endocrine neoplasia type 2A (MEN2A). Hum Genet. 1995 Feb;95(2):187-90. PMID:7860065
  55. ↑ Frank-Raue K, Hoppner W, Frilling A, Kotzerke J, Dralle H, Haase R, Mann K, Seif F, Kirchner R, Rendl J, Deckart HF, Ritter MM, Hampel R, Klempa J, Scholz GH, Raue F. Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group. J Clin Endocrinol Metab. 1996 May;81(5):1780-3. PMID:8626834
  56. ↑ Hoppner W, Ritter MM. A duplication of 12 bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A. Hum Mol Genet. 1997 Apr;6(4):587-90. PMID:9097963
  57. ↑ Hoppner W, Dralle H, Brabant G. Duplication of 9 base pairs in the critical cysteine-rich domain of the RET proto-oncogene causes multiple endocrine neoplasia type 2A. Hum Mutat. 1998;Suppl 1:S128-30. PMID:9452064
  58. ↑ Tessitore A, Sinisi AA, Pasquali D, Cardone M, Vitale D, Bellastella A, Colantuoni V. A novel case of multiple endocrine neoplasia type 2A associated with two de novo mutations of the RET protooncogene. J Clin Endocrinol Metab. 1999 Oct;84(10):3522-7. PMID:10522989
  59. ↑ Skinner MA, Safford SD, Reeves JG, Jackson ME, Freemerman AJ. Renal aplasia in humans is associated with RET mutations. Am J Hum Genet. 2008 Feb;82(2):344-51. Epub 2008 Jan 31. PMID:18252215 doi:S0002-9297(08)00086-4
  60. ↑ Amiel J, Salomon R, Attie T, Pelet A, Trang H, Mokhtari M, Gaultier C, Munnich A, Lyonnet S. Mutations of the RET-GDNF signaling pathway in Ondine's curse. Am J Hum Genet. 1998 Mar;62(3):715-7. PMID:9497256 doi:10.1086/301759
  61. ↑ Kanai M, Numakura C, Sasaki A, Shirahata E, Akaba K, Hashimoto M, Hasegawa H, Shirasawa S, Hayasaka K. Congenital central hypoventilation syndrome: a novel mutation of the RET gene in an isolated case. Tohoku J Exp Med. 2002 Apr;196(4):241-6. PMID:12086152
  62. ↑ Sasaki A, Kanai M, Kijima K, Akaba K, Hashimoto M, Hasegawa H, Otaki S, Koizumi T, Kusuda S, Ogawa Y, Tuchiya K, Yamamoto W, Nakamura T, Hayasaka K. Molecular analysis of congenital central hypoventilation syndrome. Hum Genet. 2003 Dec;114(1):22-6. Epub 2003 Oct 18. PMID:14566559 doi:10.1007/s00439-003-1036-z
  63. ↑ Ma Q. RETouching upon mechanoreceptors. Neuron. 2009 Dec 24;64(6):773-6. doi: 10.1016/j.neuron.2009.12.014. PMID:20064382 doi:10.1016/j.neuron.2009.12.014
  64. ↑ Garcia-Lavandeira M, Diaz-Rodriguez E, Garcia-Rendueles ME, Rodrigues JS, Perez-Romero S, Bravo SB, Alvarez CV. Functional role of the RET dependence receptor, GFRa co-receptors and ligands in the pituitary. Front Horm Res. 2010;38:127-38. doi: 10.1159/000318502. Epub 2010 Jul 5. PMID:20616503 doi:10.1159/000318502
  65. ↑ Cockburn JG, Richardson DS, Gujral TS, Mulligan LM. RET-mediated cell adhesion and migration require multiple integrin subunits. J Clin Endocrinol Metab. 2010 Nov;95(11):E342-6. doi: 10.1210/jc.2010-0771. Epub , 2010 Aug 11. PMID:20702524 doi:10.1210/jc.2010-0771
  66. ↑ Cabrera JR, Bouzas-Rodriguez J, Tauszig-Delamasure S, Mehlen P. RET modulates cell adhesion via its cleavage by caspase in sympathetic neurons. J Biol Chem. 2011 Apr 22;286(16):14628-38. doi: 10.1074/jbc.M110.195461. Epub, 2011 Feb 28. PMID:21357690 doi:10.1074/jbc.M110.195461
  67. ↑ Plaza-Menacho I, Morandi A, Mologni L, Boender P, Gambacorti-Passerini C, Magee AI, Hofstra RM, Knowles P, McDonald NQ, Isacke CM. Focal adhesion kinase (FAK) binds RET kinase via its FERM domain, priming a direct and reciprocal RET-FAK transactivation mechanism. J Biol Chem. 2011 May 13;286(19):17292-302. doi: 10.1074/jbc.M110.168500. Epub, 2011 Mar 22. PMID:21454698 doi:10.1074/jbc.M110.168500
  68. ↑ Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, Ibanez CF, McDonald NQ. Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem. 2006 Nov 3;281(44):33577-87. Epub 2006 Aug 23. PMID:16928683 doi:http://dx.doi.org/10.1074/jbc.M605604200

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