UniProt functional annotation for Q9UM73



	UniProt functional annotation for Q9UM73

UniProt code: Q9UM73.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Neuronal 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. Thinness gene involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). {ECO:0000250|UniProtKB:P97793, ECO:0000269|PubMed:11121404, ECO:0000269|PubMed:11278720, ECO:0000269|PubMed:11387242, ECO:0000269|PubMed:11809760, ECO:0000269|PubMed:12107166, ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:15908427, ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};

Activity 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. {ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:17681947, ECO:0000269|PubMed:21575866}.

Subunit: Homodimer. Homodimerizes when bound to ligand (PubMed:16317043). Interacts with CBL, IRS1, PIK3R1 and PLCG1 (PubMed:15226403). Interacts with FRS2 and SHC1 (PubMed:17274988, PubMed:16878150, PubMed:15226403). Interacts with PTN and MDK (PubMed:12122009, PubMed:11278720). {ECO:0000269|PubMed:11278720, ECO:0000269|PubMed:12122009, ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:9174053}; Single-pass type I membrane protein {ECO:0000269|PubMed:16317043, ECO:0000269|PubMed:9174053}. Note=Membrane attachment was crucial for promotion of neuron-like differentiation and cell proliferation arrest through specific activation of the MAP kinase pathway.

Tissue specificity: Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells. {ECO:0000269|PubMed:9174053}.

Ptm: Phosphorylated at tyrosine residues by autocatalysis, which activates kinase activity. In cells not stimulated by a ligand, receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) dephosphorylates ALK at the sites in ALK that are undergoing autophosphorylation through autoactivation. Phosphorylation at Tyr-1507 is critical for SHC1 association. {ECO:0000269|PubMed:11121404, ECO:0000269|PubMed:15938644, ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:17274988, ECO:0000269|PubMed:17681947}.

Ptm: N-glycosylated. {ECO:0000269|PubMed:9174053}.

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) [MIM:613014]: 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. {ECO:0000269|PubMed:18724359, ECO:0000269|PubMed:18923523, ECO:0000269|PubMed:18923525, ECO:0000269|PubMed:21242967}. Note=Disease susceptibility is associated with variants 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.

Disease: Note=A chromosomal aberration involving ALK is found in one subject with colorectal cancer. Translocation t(2;2)(p23.1;p23.3). A 5 million base pair tandem duplication generates an in-frame WDCP-ALK gene fusion. {ECO:0000269|PubMed:22327622}.

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE- ProRule:PRU00159}.

Sequence caution: Sequence=BAD92714.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Neuronal 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. Thinness gene involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). {ECO:0000250\|UniProtKB:P97793, ECO:0000269\|PubMed:11121404, ECO:0000269\|PubMed:11278720, ECO:0000269\|PubMed:11387242, ECO:0000269\|PubMed:11809760, ECO:0000269\|PubMed:12107166, ECO:0000269\|PubMed:12122009, ECO:0000269\|PubMed:15226403, ECO:0000269\|PubMed:15908427, ECO:0000269\|PubMed:16317043, ECO:0000269\|PubMed:16878150, ECO:0000269\|PubMed:17274988}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028};
Activity 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. {ECO:0000269\|PubMed:16317043, ECO:0000269\|PubMed:17681947, ECO:0000269\|PubMed:21575866}.
Subunit:		Homodimer. Homodimerizes when bound to ligand (PubMed:16317043). Interacts with CBL, IRS1, PIK3R1 and PLCG1 (PubMed:15226403). Interacts with FRS2 and SHC1 (PubMed:17274988, PubMed:16878150, PubMed:15226403). Interacts with PTN and MDK (PubMed:12122009, PubMed:11278720). {ECO:0000269\|PubMed:11278720, ECO:0000269\|PubMed:12122009, ECO:0000269\|PubMed:15226403, ECO:0000269\|PubMed:16317043, ECO:0000269\|PubMed:16878150, ECO:0000269\|PubMed:17274988}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:16317043, ECO:0000269\|PubMed:9174053}; Single-pass type I membrane protein {ECO:0000269\|PubMed:16317043, ECO:0000269\|PubMed:9174053}. Note=Membrane attachment was crucial for promotion of neuron-like differentiation and cell proliferation arrest through specific activation of the MAP kinase pathway.
Tissue specificity:		Expressed in brain and CNS. Also expressed in the small intestine and testis, but not in normal lymphoid cells. {ECO:0000269\|PubMed:9174053}.
Ptm:		Phosphorylated at tyrosine residues by autocatalysis, which activates kinase activity. In cells not stimulated by a ligand, receptor protein tyrosine phosphatase beta and zeta complex (PTPRB/PTPRZ1) dephosphorylates ALK at the sites in ALK that are undergoing autophosphorylation through autoactivation. Phosphorylation at Tyr-1507 is critical for SHC1 association. {ECO:0000269\|PubMed:11121404, ECO:0000269\|PubMed:15938644, ECO:0000269\|PubMed:16878150, ECO:0000269\|PubMed:17274988, ECO:0000269\|PubMed:17681947}.
Ptm:		N-glycosylated. {ECO:0000269\|PubMed:9174053}.
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) [MIM:613014]: 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. {ECO:0000269\|PubMed:18724359, ECO:0000269\|PubMed:18923523, ECO:0000269\|PubMed:18923525, ECO:0000269\|PubMed:21242967}. Note=Disease susceptibility is associated with variants 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.
Disease:		Note=A chromosomal aberration involving ALK is found in one subject with colorectal cancer. Translocation t(2;2)(p23.1;p23.3). A 5 million base pair tandem duplication generates an in-frame WDCP-ALK gene fusion. {ECO:0000269\|PubMed:22327622}.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily. {ECO:0000255\|PROSITE- ProRule:PRU00159}.
Sequence caution:		Sequence=BAD92714.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};