| Structural highlights
4fnx is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Related: | 4fnw, 4fny, 4fnz, 4fob, 4foc, 4fod |
| Gene: | ALK (HUMAN) |
| Activity: | Receptor protein-tyrosine kinase, with EC number 2.7.10.1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[ALK_HUMAN] Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:613014]. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.[1] [2] [3] Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.
Function
[ALK_HUMAN] Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14]
Publication Abstract from PubMed
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that, when genetically altered by mutation, amplification, chromosomal translocation or inversion, has been shown to play an oncogenic role in certain cancers. Small molecule inhibitors targeting the kinase activity of ALK have proven to be effective therapies in certain ALK-driven malignancies and one such inhibitor, crizotinib, is now approved for the treatment of EML4-ALK-driven, non-small cell lung cancer. In neuroblastoma, activating point mutations in the ALK kinase domain can drive disease progression, with the two most common mutations being F1174L and R1275Q. We report here crystal structures of the ALK kinase domain containing the F1174L and R1275Q mutations. Also included are crystal structures of ALK in complex with novel small molecule ALK inhibitors, including a classic type II inhibitor, that stabilize previously unobserved conformations of the ALK activation loop. Collectively, these structures illustrate a different series of activation loop conformations than has been observed in previous ALK crystal structures and provide insight into the activating nature of the R1275Q mutation. The novel active site topologies presented here may also aid the structure-based drug design of a new generation of ALK inhibitors.
The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase.,Epstein LF, Chen H, Emkey R, Whittington DA J Biol Chem. 2012 Oct 26;287(44):37447-57. doi: 10.1074/jbc.M112.391425. Epub, 2012 Aug 29. PMID:22932897[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mosse YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008 Oct 16;455(7215):930-5. doi: 10.1038/nature07261. Epub 2008 Aug 24. PMID:18724359 doi:10.1038/nature07261
- ↑ Janoueix-Lerosey I, Lequin D, Brugieres L, Ribeiro A, de Pontual L, Combaret V, Raynal V, Puisieux A, Schleiermacher G, Pierron G, Valteau-Couanet D, Frebourg T, Michon J, Lyonnet S, Amiel J, Delattre O. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008 Oct 16;455(7215):967-70. doi: 10.1038/nature07398. PMID:18923523 doi:10.1038/nature07398
- ↑ George RE, Sanda T, Hanna M, Frohling S, Luther W 2nd, Zhang J, Ahn Y, Zhou W, London WB, McGrady P, Xue L, Zozulya S, Gregor VE, Webb TR, Gray NS, Gilliland DG, Diller L, Greulich H, Morris SW, Meyerson M, Look AT. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature. 2008 Oct 16;455(7215):975-8. doi: 10.1038/nature07397. PMID:18923525 doi:10.1038/nature07397
- ↑ Simonitsch I, Polgar D, Hajek M, Duchek P, Skrzypek B, Fassl S, Lamprecht A, Schmidt G, Krupitza G, Cerni C. The cytoplasmic truncated receptor tyrosine kinase ALK homodimer immortalizes and cooperates with ras in cellular transformation. FASEB J. 2001 Jun;15(8):1416-8. PMID:11387242
- ↑ Souttou B, Carvalho NB, Raulais D, Vigny M. Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway. J Biol Chem. 2001 Mar 23;276(12):9526-31. Epub 2000 Dec 19. PMID:11121404 doi:10.1074/jbc.M007333200
- ↑ Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A. Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem. 2001 May 18;276(20):16772-9. Epub 2001 Feb 8. PMID:11278720 doi:10.1074/jbc.M010660200
- ↑ Powers C, Aigner A, Stoica GE, McDonnell K, Wellstein A. Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth. J Biol Chem. 2002 Apr 19;277(16):14153-8. Epub 2002 Jan 23. PMID:11809760 doi:10.1074/jbc.M112354200
- ↑ Bowden ET, Stoica GE, Wellstein A. Anti-apoptotic signaling of pleiotrophin through its receptor, anaplastic lymphoma kinase. J Biol Chem. 2002 Sep 27;277(39):35862-8. Epub 2002 Jul 9. PMID:12107166 doi:10.1074/jbc.M203963200
- ↑ Stoica GE, Kuo A, Powers C, Bowden ET, Sale EB, Riegel AT, Wellstein A. Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J Biol Chem. 2002 Sep 27;277(39):35990-8. Epub 2002 Jul 16. PMID:12122009 doi:10.1074/jbc.M205749200
- ↑ Motegi A, Fujimoto J, Kotani M, Sakuraba H, Yamamoto T. ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth. J Cell Sci. 2004 Jul 1;117(Pt 15):3319-29. PMID:15226403 doi:10.1242/jcs.01183
- ↑ Lu KV, Jong KA, Kim GY, Singh J, Dia EQ, Yoshimoto K, Wang MY, Cloughesy TF, Nelson SF, Mischel PS. Differential induction of glioblastoma migration and growth by two forms of pleiotrophin. J Biol Chem. 2005 Jul 22;280(29):26953-64. Epub 2005 May 20. PMID:15908427 doi:10.1074/jbc.M502614200
- ↑ Gouzi JY, Moog-Lutz C, Vigny M, Brunet-de Carvalho N. Role of the subcellular localization of ALK tyrosine kinase domain in neuronal differentiation of PC12 cells. J Cell Sci. 2005 Dec 15;118(Pt 24):5811-23. Epub 2005 Nov 29. PMID:16317043 doi:10.1242/jcs.02695
- ↑ Degoutin J, Vigny M, Gouzi JY. ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation. FEBS Lett. 2007 Feb 20;581(4):727-34. Epub 2007 Jan 25. PMID:17274988 doi:10.1016/j.febslet.2007.01.039
- ↑ Kuo AH, Stoica GE, Riegel AT, Wellstein A. Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase. Oncogene. 2007 Feb 8;26(6):859-69. Epub 2006 Jul 31. PMID:16878150 doi:10.1038/sj.onc.1209840
- ↑ Epstein LF, Chen H, Emkey R, Whittington DA. The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase. J Biol Chem. 2012 Oct 26;287(44):37447-57. doi: 10.1074/jbc.M112.391425. Epub, 2012 Aug 29. PMID:22932897 doi:http://dx.doi.org/10.1074/jbc.M112.391425
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