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==FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 4-{[4-{[(1R,2R)-2-(dimethylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-N-methylbenzenesulfonamide==
==FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 4-{[4-{[(1R,2R)-2-(dimethylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-N-methylbenzenesulfonamide==
<StructureSection load='6yvy' size='340' side='right'caption='[[6yvy]]' scene=''>
<StructureSection load='6yvy' size='340' side='right'caption='[[6yvy]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YVY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YVY FirstGlance]. <br>
<table><tr><td colspan='2'>[[6yvy]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YVY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YVY FirstGlance]. <br>
</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=6yvy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yvy OCA], [https://pdbe.org/6yvy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yvy RCSB], [https://www.ebi.ac.uk/pdbsum/6yvy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yvy ProSAT]</span></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=P1E:4-{[4-{[(1R,2R)-2-(DIMETHYLAMINO)CYCLOPENTYL]AMINO}-5-(TRIFLUOROMETHYL)PYRIMIDIN-2-YL]AMINO}-N-METHYLBENZENESULFONAMIDE'>P1E</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTK2, FAK, FAK1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></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=6yvy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yvy OCA], [https://pdbe.org/6yvy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yvy RCSB], [https://www.ebi.ac.uk/pdbsum/6yvy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yvy ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.<ref>PMID:11980671</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:17431114</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref> 
== Function ==
[[https://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.<ref>PMID:10655584</ref> <ref>PMID:11331870</ref> <ref>PMID:11980671</ref> <ref>PMID:15166238</ref> <ref>PMID:15561106</ref> <ref>PMID:15895076</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:16927379</ref> <ref>PMID:17431114</ref> <ref>PMID:18497331</ref> <ref>PMID:18292575</ref> <ref>PMID:18256281</ref> <ref>PMID:18206965</ref> <ref>PMID:19138410</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:20109444</ref> <ref>PMID:21454698</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2.
Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2.,Berger BT, Amaral M, Kokh DB, Nunes-Alves A, Musil D, Heinrich T, Schroder M, Neil R, Wang J, Navratilova I, Bomke J, Elkins JM, Muller S, Frech M, Wade RC, Knapp S Cell Chem Biol. 2021 Jan 21. pii: S2451-9456(21)00003-9. doi:, 10.1016/j.chembiol.2021.01.003. PMID:33497606<ref>PMID:33497606</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6yvy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Amaral M]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Musil D]]
[[Category: Amaral, M]]
[[Category: Musil, D]]
[[Category: Atp binding]]
[[Category: Protein tyrosine kinase]]
[[Category: Transferase]]
[[Category: Transferase-inhibitor complex]]

Revision as of 17:46, 2 June 2021

FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 4-{[4-{[(1R,2R)-2-(dimethylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-N-methylbenzenesulfonamideFOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 4-{[4-{[(1R,2R)-2-(dimethylamino)cyclopentyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-N-methylbenzenesulfonamide

Structural highlights

6yvy is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:PTK2, FAK, FAK1 (HUMAN)
Activity:Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[FAK1_HUMAN] Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.[1] [2] [3] [4] [5] [6] [7] [8] [9]

Function

[FAK1_HUMAN] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31]

Publication Abstract from PubMed

There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2.

Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2.,Berger BT, Amaral M, Kokh DB, Nunes-Alves A, Musil D, Heinrich T, Schroder M, Neil R, Wang J, Navratilova I, Bomke J, Elkins JM, Muller S, Frech M, Wade RC, Knapp S Cell Chem Biol. 2021 Jan 21. pii: S2451-9456(21)00003-9. doi:, 10.1016/j.chembiol.2021.01.003. PMID:33497606[32]

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

References

  1. ↑ Hecker TP, Grammer JR, Gillespie GY, Stewart J Jr, Gladson CL. Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples. Cancer Res. 2002 May 1;62(9):2699-707. PMID:11980671
  2. ↑ Halder J, Lin YG, Merritt WM, Spannuth WA, Nick AM, Honda T, Kamat AA, Han LY, Kim TJ, Lu C, Tari AM, Bornmann W, Fernandez A, Lopez-Berestein G, Sood AK. Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. Cancer Res. 2007 Nov 15;67(22):10976-83. PMID:18006843 doi:10.1158/0008-5472.CAN-07-2667
  3. ↑ Slack-Davis JK, Martin KH, Tilghman RW, Iwanicki M, Ung EJ, Autry C, Luzzio MJ, Cooper B, Kath JC, Roberts WG, Parsons JT. Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007 May 18;282(20):14845-52. Epub 2007 Mar 28. PMID:17395594 doi:10.1074/jbc.M606695200
  4. ↑ Liu TJ, LaFortune T, Honda T, Ohmori O, Hatakeyama S, Meyer T, Jackson D, de Groot J, Yung WK. Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther. 2007 Apr;6(4):1357-67. PMID:17431114 doi:10.1158/1535-7163.MCT-06-0476
  5. ↑ Pylayeva Y, Gillen KM, Gerald W, Beggs HE, Reichardt LF, Giancotti FG. Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J Clin Invest. 2009 Feb;119(2):252-66. doi: 10.1172/JCI37160. Epub 2009 Jan 19. PMID:19147981 doi:10.1172/JCI37160
  6. ↑ Sun H, Pisle S, Gardner ER, Figg WD. Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models. Cancer Biol Ther. 2010 Jul 1;10(1):38-43. Epub 2010 Jul 9. PMID:20495381
  7. ↑ Mitra SK, Schlaepfer DD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006 Oct;18(5):516-23. Epub 2006 Aug 17. PMID:16919435 doi:10.1016/j.ceb.2006.08.011
  8. ↑ Lim ST, Mikolon D, Stupack DG, Schlaepfer DD. FERM control of FAK function: implications for cancer therapy. Cell Cycle. 2008 Aug;7(15):2306-14. Epub 2008 May 29. PMID:18677107
  9. ↑ Golubovskaya VM, Kweh FA, Cance WG. Focal adhesion kinase and cancer. Histol Histopathol. 2009 Apr;24(4):503-10. PMID:19224453
  10. ↑ Miao H, Burnett E, Kinch M, Simon E, Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000 Feb;2(2):62-9. PMID:10655584 doi:10.1038/35000008
  11. ↑ Chen R, Kim O, Li M, Xiong X, Guan JL, Kung HJ, Chen H, Shimizu Y, Qiu Y. Regulation of the PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain. Nat Cell Biol. 2001 May;3(5):439-44. PMID:11331870 doi:10.1038/35074500
  12. ↑ Hecker TP, Grammer JR, Gillespie GY, Stewart J Jr, Gladson CL. Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples. Cancer Res. 2002 May 1;62(9):2699-707. PMID:11980671
  13. ↑ Xia H, Nho RS, Kahm J, Kleidon J, Henke CA. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem. 2004 Jul 30;279(31):33024-34. Epub 2004 May 27. PMID:15166238 doi:10.1074/jbc.M313265200
  14. ↑ Continolo S, Baruzzi A, Majeed M, Caveggion E, Fumagalli L, Lowell CA, Berton G. The proto-oncogene Fgr regulates cell migration and this requires its plasma membrane localization. Exp Cell Res. 2005 Jan 15;302(2):253-69. PMID:15561106 doi:10.1016/j.yexcr.2004.09.005
  15. ↑ Ezratty EJ, Partridge MA, Gundersen GG. Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase. Nat Cell Biol. 2005 Jun;7(6):581-90. Epub 2005 May 15. PMID:15895076 doi:10.1038/ncb1262
  16. ↑ Halder J, Lin YG, Merritt WM, Spannuth WA, Nick AM, Honda T, Kamat AA, Han LY, Kim TJ, Lu C, Tari AM, Bornmann W, Fernandez A, Lopez-Berestein G, Sood AK. Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. Cancer Res. 2007 Nov 15;67(22):10976-83. PMID:18006843 doi:10.1158/0008-5472.CAN-07-2667
  17. ↑ Slack-Davis JK, Martin KH, Tilghman RW, Iwanicki M, Ung EJ, Autry C, Luzzio MJ, Cooper B, Kath JC, Roberts WG, Parsons JT. Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007 May 18;282(20):14845-52. Epub 2007 Mar 28. PMID:17395594 doi:10.1074/jbc.M606695200
  18. ↑ Salasznyk RM, Klees RF, Boskey A, Plopper GE. Activation of FAK is necessary for the osteogenic differentiation of human mesenchymal stem cells on laminin-5. J Cell Biochem. 2007 Feb 1;100(2):499-514. PMID:16927379 doi:10.1002/jcb.21074
  19. ↑ Liu TJ, LaFortune T, Honda T, Ohmori O, Hatakeyama S, Meyer T, Jackson D, de Groot J, Yung WK. Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo. Mol Cancer Ther. 2007 Apr;6(4):1357-67. PMID:17431114 doi:10.1158/1535-7163.MCT-06-0476
  20. ↑ Sundberg-Smith LJ, DiMichele LA, Sayers RL, Mack CP, Taylor JM. The LIM protein leupaxin is enriched in smooth muscle and functions as an serum response factor cofactor to induce smooth muscle cell gene transcription. Circ Res. 2008 Jun 20;102(12):1502-11. doi: 10.1161/CIRCRESAHA.107.170357. Epub, 2008 May 22. PMID:18497331 doi:10.1161/CIRCRESAHA.107.170357
  21. ↑ Semaan N, Alsaleh G, Gottenberg JE, Wachsmann D, Sibilia J. Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways. J Immunol. 2008 Mar 1;180(5):3485-91. PMID:18292575
  22. ↑ Singh MK, Dadke D, Nicolas E, Serebriiskii IG, Apostolou S, Canutescu A, Egleston BL, Golemis EA. A novel Cas family member, HEPL, regulates FAK and cell spreading. Mol Biol Cell. 2008 Apr;19(4):1627-36. Epub 2008 Feb 6. PMID:18256281 doi:E07-09-0953
  23. ↑ Lim ST, Chen XL, Lim Y, Hanson DA, Vo TT, Howerton K, Larocque N, Fisher SJ, Schlaepfer DD, Ilic D. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell. 2008 Jan 18;29(1):9-22. doi: 10.1016/j.molcel.2007.11.031. PMID:18206965 doi:10.1016/j.molcel.2007.11.031
  24. ↑ Sachdev S, Bu Y, Gelman IH. Paxillin-Y118 phosphorylation contributes to the control of Src-induced anchorage-independent growth by FAK and adhesion. BMC Cancer. 2009 Jan 12;9:12. doi: 10.1186/1471-2407-9-12. PMID:19138410 doi:10.1186/1471-2407-9-12
  25. ↑ Pylayeva Y, Gillen KM, Gerald W, Beggs HE, Reichardt LF, Giancotti FG. Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J Clin Invest. 2009 Feb;119(2):252-66. doi: 10.1172/JCI37160. Epub 2009 Jan 19. PMID:19147981 doi:10.1172/JCI37160
  26. ↑ Sun H, Pisle S, Gardner ER, Figg WD. Bioluminescent imaging study: FAK inhibitor, PF-562,271, preclinical study in PC3M-luc-C6 local implant and metastasis xenograft models. Cancer Biol Ther. 2010 Jul 1;10(1):38-43. Epub 2010 Jul 9. PMID:20495381
  27. ↑ Cai GQ, Zheng A, Tang Q, White ES, Chou CF, Gladson CL, Olman MA, Ding Q. Downregulation of FAK-related non-kinase mediates the migratory phenotype of human fibrotic lung fibroblasts. Exp Cell Res. 2010 May 15;316(9):1600-9. doi: 10.1016/j.yexcr.2010.01.021. Epub, 2010 Jan 25. PMID:20109444 doi:10.1016/j.yexcr.2010.01.021
  28. ↑ 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
  29. ↑ Mitra SK, Schlaepfer DD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006 Oct;18(5):516-23. Epub 2006 Aug 17. PMID:16919435 doi:10.1016/j.ceb.2006.08.011
  30. ↑ Lim ST, Mikolon D, Stupack DG, Schlaepfer DD. FERM control of FAK function: implications for cancer therapy. Cell Cycle. 2008 Aug;7(15):2306-14. Epub 2008 May 29. PMID:18677107
  31. ↑ Golubovskaya VM, Kweh FA, Cance WG. Focal adhesion kinase and cancer. Histol Histopathol. 2009 Apr;24(4):503-10. PMID:19224453
  32. ↑ Berger BT, Amaral M, Kokh DB, Nunes-Alves A, Musil D, Heinrich T, Schroder M, Neil R, Wang J, Navratilova I, Bomke J, Elkins JM, Muller S, Frech M, Wade RC, Knapp S. Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2. Cell Chem Biol. 2021 Jan 21. pii: S2451-9456(21)00003-9. doi:, 10.1016/j.chembiol.2021.01.003. PMID:33497606 doi:http://dx.doi.org/10.1016/j.chembiol.2021.01.003

6yvy, resolution 1.92Å

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