ALK_HUMAN » ALK tyrosine kinase receptor

ALK_HUMAN » ALK tyrosine kinase receptor
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
ALK_HUMAN » ALK tyrosine kinase receptor » Anaplastic lymphoma kinase;
Hydrophobic Thickness 40.8 ± 1.2 Å
Tilt Angle 6 ± 2°
ΔGtransfer -60.6 kcal/mol
ΔGfold -22.1 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 1031-1059 (1030-1063)
Pathways

colanic acid building blocks biosynthesis (BioCyc)

galactose degradation I (Leloir pathway) (BioCyc)

PDB 4fob (1058-1410), 4foc (1058-1410), 3aox (1069-1411), 3lct (1072-1410), 3lcs (1072-1410), 3l9p (1072-1410), 4mkc (1072-1410), 4joa (1072-1410), 4fod (1078-1410), 4dce (1078-1410), 4fnz (1084-1410), 4fnw (1084-1410), 4fnx (1084-1410), 4fny (1084-1410), 4clj (1093-1411), 4cmo (1093-1411), 4cmt (1093-1411), 4cmu (1093-1411), 4cnh (1093-1411), 4ctc (1093-1411), 4ctb (1093-1411), 4cli (1093-1411), 4ccu (1093-1411), 2xp2 (1093-1411), 2yfx (1093-1411), 2yhv (1093-1411), 2yjr (1093-1411), 2yjs (1093-1411), 4anl (1093-1411), 4anq (1093-1411), 4ans (1093-1411), 4ccb (1093-1411), 4cd0 (1093-1411), 2xba (1094-1407), 2xb7 (1094-1407), 4tt7 (1095-1410), 2yt2 (1571-1589), 2kuq (1571-1589), 2ys5 (B=1571-1589), 2kup (B=1571-1589)
OPM none
Complexes none
Interactions

1B07, Complex: ALK:1B07, PubMed

EPHA1, Complex: EPHA1:ALK, PubMed

EPHB2, Complex: EPHB2:ALK, PubMed

EPHB3, Complex: ALK:EPHB3, PubMed

MEP1B, Complex: ALK:MEP1B, PubMed

PTPRB, Complex: ALK:PTPRB

PTPRG, Complex: ALK:PTPRG

PTPRJ, Complex: ALK:PTPRJ

PTPRK, Complex: ALK:PTPRK, PubMed

PTPRZ, Complex: ALK:PTPRZ, PubMed

TNR8, Complex: TNR8:ALK, PubMed

Domains

AA: 266-426, PDBID: 2C9A, Subunit A, Seq Identity:21%, MAM domain, meprin/A5/mu

AA: 480-635, PDBID: 4GWM, Subunit A, Seq Identity:18%, MAM domain, meprin/A5/mu

AA: 726-992, Glycine rich protein

AA: 1116-1383, PDBID: 2XB7, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for ALK_HUMAN » ALK tyrosine kinase receptor
FUNCTION: 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.

CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

ENZYME REGULATION: Activated by ligand-binding and subsequent phosphorylation. Inactivated through dephosphorylation by receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) when there is no stimulation by a ligand. Staurosporine, crizotinib and CH5424802 act as inhibitors of ALK kinase activity.

SUBUNIT: Homodimer. Homodimerizes when bound to ligand. Interacts with FRS2, IRS1, MDK, PTN and SHC1. Interacts with CBL, PIK3R1 and PLCG1 (By similarity).

TISSUE SPECIFICITY: Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells.

DISEASE: 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.

DISEASE: 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.

DISEASE: Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17.

DISEASE: Neuroblastoma 3 (NBLST3) OMIM: 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. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.

DISEASE: 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.

UniProt features for ALK_HUMAN » ALK tyrosine kinase receptor
SIGNAL 1 18 Potential.
CHAIN 19 1620 ALK tyrosine kinase receptor.
DOMAIN 264 427 MAM 1.
DOMAIN 437 473 LDL-receptor class A.
DOMAIN 478 636 MAM 2.
DOMAIN 1116 1392 Protein kinase.
REGION 1197 1199 Inhibitor binding.
ACT_SITE 1249 1249 Proton acceptor (By similarity).
Amino Acid Sequence for ALK_HUMAN » ALK tyrosine kinase receptor
MGAIGLLWLL PLLLSTAAVG SGMGTGQRAG SPAAGPPLQP REPLSYSRLQ RKSLAVDFVV PSLFRVYARD LLLPPSSSEL KAGRPEARGS LALDCAPLLR LLGPAPGVSW TAGSPAPAEA RTLSRVLKGG SVRKLRRAKQ LVLELGEEAI LEGCVGPPGE AAVGLLQFNL SELFSWWIRQ GEGRLRIRLM PEKKASEVGR EGRLSAAIRA SQPRLLFQIF GTGHSSLESP TNMPSPSPDY FTWNLTWIMK DSFPFLSHRS RYGLECSFDF PCELEYSPPL HDLRNQSWSW RRIPSEEASQ MDLLDGPGAE RSKEMPRGSF LLLNTSADSK HTILSPWMRS SSEHCTLAVS VHRHLQPSGR YIAQLLPHNE AAREILLMPT PGKHGWTVLQ GRIGRPDNPF RVALEYISSG NRSLSAVDFF ALKNCSEGTS PGSKMALQSS FTCWNGTVLQ LGQACDFHQD CAQGEDESQM CRKLPVGFYC NFEDGFCGWT QGTLSPHTPQ WQVRTLKDAR FQDHQDHALL LSTTDVPASE SATVTSATFP APIKSSPCEL RMSWLIRGVL RGNVSLVLVE NKTGKEQGRM VWHVAAYEGL SLWQWMVLPL LDVSDRFWLQ MVAWWGQGSR AIVAFDNISI SLDCYLTISG EDKILQNTAP KSRNLFERNP NKELKPGENS PRQTPIFDPT VHWLFTTCGA SGPHGPTQAQ CNNAYQNSNL SVEVGSEGPL KGIQIWKVPA TDTYSISGYG AAGGKGGKNT MMRSHGVSVL GIFNLEKDDM LYILVGQQGE DACPSTNQLI QKVCIGENNV IEEEIRVNRS VHEWAGGGGG GGGATYVFKM KDGVPVPLII AAGGGGRAYG AKTDTFHPER LENNSSVLGL NGNSGAAGGG GGWNDNTSLL WAGKSLQEGA TGGHSCPQAM KKWGWETRGG FGGGGGGCSS GGGGGGYIGG NAASNNDPEM DGEDGVSFIS PLGILYTPAL KVMEGHGEVN IKHYLNCSHC EVDECHMDPE SHKVICFCDH GTVLAEDGVS CIVSPTPEPH LPLSLILSVV TSALVAALVL AFSGIMIVYR RKHQELQAMQ MELQSPEYKL SKLRTSTIMT DYNPNYCFAG KTSSISDLKE VPRKNITLIR GLGHGAFGEV YEGQVSGMPN DPSPLQVAVK TLPEVCSEQD ELDFLMEALI ISKFNHQNIV RCIGVSLQSL PRFILLELMA GGDLKSFLRE TRPRPSQPSS LAMLDLLHVA RDIACGCQYL EENHFIHRDI AARNCLLTCP GPGRVAKIGD FGMARDIYRA SYYRKGGCAM LPVKWMPPEA FMEGIFTSKT DTWSFGVLLW EIFSLGYMPY PSKSNQEVLE FVTSGGRMDP PKNCPGPVYR IMTQCWQHQP EDRPNFAIIL ERIEYCTQDP DVINTALPIE YGPLVEEEEK VPVRPKDPEG VPPLLVSQQA KREEERSPAA PPPLPTTSSG KAAKKPTAAE VSVRVPRGPA VEGGHVNMAF SQSNPPSELH KVHGSRNKPT SLWNPTYGSW FTEKPTKKNN PIAKKEPHDR GNLGLEGSCT VPPNVATGRL PGASLLLEPS SLTANMKEVP LFRLRHFPCG NVNYGYQQQG LPLEAATAPG AGHYEDTILK SKNSMNQPGP