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== Extracellular Domain Binding == | == Extracellular Domain Binding == | ||
=== Ligands === | === Ligands === | ||
The extracellular ligands of ALK are | The extracellular ligands of ALK are Anaplastic Lymphoma Kinase Ligand 2 (ALKAL 2) and Anaplastic Lymphoma Kinase Ligand 1 (ALKAL 1). | ||
==== ALKAL2 ==== | ==== ALKAL2 ==== | ||
<scene name='90/904331/Alkal2/3'>ALKAL2</scene> | <scene name='90/904331/Alkal2/3'>ALKAL2</scene> is a ligand of ALK as well as LTK located in the extracellular region. The full-length ALKAL2 (dimeric) and ALKAL2-AD (monomeric) can both induce dimerization of ALK <ref name="Reshetnyak">PMID:34819673</ref>. Structurally, ALKAL2 has a N-termical variable region and a conserved augmentor domain and tends to aggregate in the cell <ref name="Reshetnyak" />. Overexpression of ALKAL2 has been linked to high-risk [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma] in absence of an ALK mutation <ref name="Borenas">PMID:33411331</ref> and could potentially have therapeutic opportunities. | ||
==== ALKAL1 ==== | ==== ALKAL1 ==== | ||
<scene name='90/904331/Alkal1/5'>ALKAL1</scene> | <scene name='90/904331/Alkal1/5'>ALKAL1</scene> is a monomeric ligand of ALK, in addition to ALKAL2. Structurally, ALKAL1 and ALKAL2 contain an N-terminal variable region and a conserved C-terminal augmentor domain <ref name="Reshetnyak" />. However, in ALKAL1, this N-terminal variable region is shorter, and shares no similar sequences to ALKAL2. Nevertheless, ALKAL1 shares a 91% sequence similarity with ALKAL2. Both ligands include a three helix bundle domain in their structures, with an extended positively charged surface which is used in ligand binding <ref name="Reshetnyak" />. ALKAL1 as a monomer, however, binds to ALK with poor stability<ref name ="Chen">PMID:33391411</ref> and was only found to stimulate ALK dimerization at much higher concentrations than ALKAL2.<ref name="Reshetnyak2">PMID:26630010</ref> | ||
=== Binding Site === | === Binding Site === | ||
This site doesn't start out surrounding the [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand], instead the proximity of the ligand allows [https://en.wikipedia.org/wiki/Conformational_change conformational changes] across the protein. The ligands for ALK both have highly positively charged faces that interact with the TNF-like region, the primary ligand-binding site on the extracellular region<ref name="Li" />. [https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) Salt bridges] between the positively charged residues on the ligand and negatively charged residues on the receptor form are formed as the ligand approaches connecting the ligand with the receptor. Three of these <scene name='90/904331/Salt_bridge_overview/1'>salt bridges</scene> occur between <scene name='90/904331/Salt_bridge_859_140/3'>E859 and R140</scene>, <scene name='90/904331/Salt_bridge_974_136/4'>E974 and R136</scene>, and <scene name='90/904331/Salt_bridge_978_123_133/3'>E978 with both R123 and R133</scene>. These strong ionic interactions allow the drastic conformational changes in the extracellular domain that induce the signaling pathway. <ref name="Reshetnyak" /> | This site doesn't start out surrounding the [https://en.wikipedia.org/wiki/Ligand_(biochemistry) ligand], instead the proximity of the ligand allows [https://en.wikipedia.org/wiki/Conformational_change conformational changes] across the protein. The ligands for ALK both have highly positively charged faces that interact with the TNF-like region, the primary ligand-binding site on the extracellular region<ref name="Li" />. [https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) Salt bridges] between the positively charged residues on the ligand and negatively charged residues on the receptor form are formed as the ligand approaches connecting the ligand with the receptor. Three of these <scene name='90/904331/Salt_bridge_overview/1'>salt bridges</scene> occur between <scene name='90/904331/Salt_bridge_859_140/3'>E859 and R140</scene>, <scene name='90/904331/Salt_bridge_974_136/4'>E974 and R136</scene>, and <scene name='90/904331/Salt_bridge_978_123_133/3'>E978 with both R123 and R133</scene>. These strong ionic interactions allow the drastic conformational changes in the extracellular domain that induce the signaling pathway. <ref name="Reshetnyak" /> | ||
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Mutations in ALK can produce oncogenic activity and are a leading factor in the development of some pediatric neuroblastoma cases<ref name="Borenas" />. 8-10% of primary neuroblastoma patients are ALK positive<ref name="Borenas" /> suggesting that ALK overstimulation is a primary factor in propagating the growth of neuroblastoma. This overstimulation of ALK works in concert with the neural MYC oncogene, and uses the ALKAL2 ligand. Tyrosine kinase inhibitors are proposed to inhibit the growth of further neuroblastoma cells, creating a potential pathway of treatment<ref name="Borenas" /> | Mutations in ALK can produce oncogenic activity and are a leading factor in the development of some pediatric neuroblastoma cases<ref name="Borenas" />. 8-10% of primary neuroblastoma patients are ALK positive<ref name="Borenas" /> suggesting that ALK overstimulation is a primary factor in propagating the growth of neuroblastoma. This overstimulation of ALK works in concert with the neural MYC oncogene, and uses the ALKAL2 ligand. Tyrosine kinase inhibitors are proposed to inhibit the growth of further neuroblastoma cells, creating a potential pathway of treatment<ref name="Borenas" /> | ||
== Inhibition | == Inhibition and Regulation == | ||
The regulation of ALK dimerization by ALKAL points to one clear way of inhibiting ALK activity and may offer new therapeutic strategies in multiple disease settings <ref name="Li">PMID:34819665</ref>. As the dimerization of ALK is essential for activation of this protein, the inhibition of this activation is a potent way of inhibiting further ALK activity.<ref name ="Li" /> The inhibition and regulation of this extracellular region of ALK is actively being explored, as this part of ALK is part of what distinguishes it from other RTKs, like LTK. Researchers are currently exploring the use of [https://proteopedia.org/wiki/index.php/Antibody antibodies] and more specifically [https://proteopedia.org/wiki/index.php/Monoclonal_Antibody#:~:text=Monoclonal%20antibodies%20are%20immunoglobulins%20produced,pure%20homogeneous%20type%20of%20antibody. monoclonal antibodies]<ref name="Carpenter">PMID: 22266870</ref> as a means of inhibiting the activity of ALK through the extracellular domain. It is hypothesized that these monoclonal antibodies act by binding to the binding site of ALK, thus preventing ALKAL from binding<ref name="Li">, and thus induces cytotoxicity to the cancerous cell itself.<ref name ="Carpenter"> | The regulation of ALK dimerization by ALKAL points to one clear way of inhibiting ALK activity and may offer new therapeutic strategies in multiple disease settings <ref name="Li">PMID:34819665</ref>. As the dimerization of ALK is essential for activation of this protein, the inhibition of this activation is a potent way of inhibiting further ALK activity.<ref name ="Li" /> The inhibition and regulation of this extracellular region of ALK is actively being explored, as this part of ALK is part of what distinguishes it from other RTKs, like LTK. Researchers are currently exploring the use of [https://proteopedia.org/wiki/index.php/Antibody antibodies] and more specifically [https://proteopedia.org/wiki/index.php/Monoclonal_Antibody#:~:text=Monoclonal%20antibodies%20are%20immunoglobulins%20produced,pure%20homogeneous%20type%20of%20antibody. monoclonal antibodies]<ref name="Carpenter">PMID: 22266870</ref> as a means of inhibiting the activity of ALK through the extracellular domain. It is hypothesized that these monoclonal antibodies act by binding to the binding site of ALK, thus preventing ALKAL from binding<ref name="Li"/>, and thus induces cytotoxicity to the cancerous cell itself.<ref name ="Carpenter"/> | ||
In colorectal cancer specifically, it has been found that gene silencing for ALKAL1 is a method of stopping tumorigenesis as in those cell lines there was an upregulation of ALKAL1, stimulating the overexpression of the ALK gene.<ref name="Chen" /> This gene silencing method was shown to stop the [https://en.wikipedia.org/wiki/Hedgehog_signaling_pathway Sonic Hedgehog signaling pathway], which is important in initial neural development and is an important signaling pathway in some cancerous cell lines when misregulated.<ref name="Chen" /> These methods of ALK dimerization inhibition show extensive promise in the field of cancer research, and demonstrate ways that the binding of ALKAL1 and ALKAL2 can be inhibited. | |||
</StructureSection>. | </StructureSection>. | ||
== References == | == References == | ||
<references/> | <references/> | ||