UniProt functional annotation for Q14680



	UniProt functional annotation for Q14680

UniProt code: Q14680.

Organism: Homo sapiens (Human).

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

Function: Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis. {ECO:0000269|PubMed:11802789, ECO:0000269|PubMed:12400006, ECO:0000269|PubMed:14699119, ECO:0000269|PubMed:15908796, ECO:0000269|PubMed:16216881, ECO:0000269|PubMed:17280616}.

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=2.7.10.2; Evidence={ECO:0000255|PROSITE-ProRule:PRU10027, ECO:0000269|PubMed:16216881};

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:16216881};

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:16216881};

Activity regulation: Activated by autophosphorylation of the T-loop at Thr-167 and Ser-171: in contrast to other members of the SNF1 subfamily, phosphorylation at Thr-167 is not mediated by STK11/LKB1 but via autophosphorylation instead. Inhibited by calcium-binding. Kinase activity is also regulated by reducing agents: dithiothreitol (DTT) or reduced glutathione are required for kinase activity in vitro; such dependence is however not due to the presence of disulfide bonds. {ECO:0000269|PubMed:16216881}.

Subunit: Monomer. Interacts with ZNF622 and PPP1R8. {ECO:0000269|PubMed:11802789, ECO:0000269|PubMed:14699119}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:16159311, ECO:0000269|PubMed:21145462}; Peripheral membrane protein {ECO:0000269|PubMed:16159311, ECO:0000269|PubMed:21145462}.

Tissue specificity: Expressed in placenta, kidney, thymus, testis, ovary and intestine. {ECO:0000269|PubMed:8724849}.

Developmental stage: Increases during G2/M phase compared to interphase. Protein level decreases when cells exit mitosis, probably due to degradation. {ECO:0000269|PubMed:20420823}.

Induction: Up-regulated in many cancers cells. Up-regulated upon treatment with radiation or 5-fluorouracil (5-FU) in colorectal cancer cells, suggesting that it might be associated with increased resistance of colorectal cells against radiation and 5-FU. Down-regulated upon siomycin A, a thiazole antibiotic, treatment, leading to inhibit tumor growth in vivo. {ECO:0000269|PubMed:21558073, ECO:0000269|PubMed:21806965}.

Domain: The KA1 domain mediates binding to phospholipids and targeting to membranes. {ECO:0000250}.

Ptm: Autophosphorylated: autophosphorylation of the T-loop at Thr-167 and Ser-171 is required for activation. Thr-478 phosphorylation during mitosis promotes interaction with PPP1R8 (Probable). {ECO:0000305|PubMed:14699119, ECO:0000305|PubMed:14976552, ECO:0000305|PubMed:16216881, ECO:0000305|PubMed:16628004, ECO:0000305|PubMed:20420823}.

Disease: Note=Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor- initiating cells and proliferation via its function in cell proliferation regulation.

Miscellaneous: Potential therapeutic target for treatment of somatic tumors, such as brain and breast cancers, down-regulation of MELK inhibiting tumorigenesis (PubMed:17960622, PubMed:20861186). {ECO:0000305|PubMed:17960622, ECO:0000305|PubMed:20861186}.

Similarity: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily. {ECO:0000305}.

Sequence caution: Sequence=BAA11492.2; 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:		Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis. {ECO:0000269\|PubMed:11802789, ECO:0000269\|PubMed:12400006, ECO:0000269\|PubMed:14699119, ECO:0000269\|PubMed:15908796, ECO:0000269\|PubMed:16216881, ECO:0000269\|PubMed:17280616}.


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=2.7.10.2; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10027, ECO:0000269\|PubMed:16216881};
Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269\|PubMed:16216881};
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269\|PubMed:16216881};
Activity regulation:		Activated by autophosphorylation of the T-loop at Thr-167 and Ser-171: in contrast to other members of the SNF1 subfamily, phosphorylation at Thr-167 is not mediated by STK11/LKB1 but via autophosphorylation instead. Inhibited by calcium-binding. Kinase activity is also regulated by reducing agents: dithiothreitol (DTT) or reduced glutathione are required for kinase activity in vitro; such dependence is however not due to the presence of disulfide bonds. {ECO:0000269\|PubMed:16216881}.
Subunit:		Monomer. Interacts with ZNF622 and PPP1R8. {ECO:0000269\|PubMed:11802789, ECO:0000269\|PubMed:14699119}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:16159311, ECO:0000269\|PubMed:21145462}; Peripheral membrane protein {ECO:0000269\|PubMed:16159311, ECO:0000269\|PubMed:21145462}.
Tissue specificity:		Expressed in placenta, kidney, thymus, testis, ovary and intestine. {ECO:0000269\|PubMed:8724849}.
Developmental stage:		Increases during G2/M phase compared to interphase. Protein level decreases when cells exit mitosis, probably due to degradation. {ECO:0000269\|PubMed:20420823}.
Induction:		Up-regulated in many cancers cells. Up-regulated upon treatment with radiation or 5-fluorouracil (5-FU) in colorectal cancer cells, suggesting that it might be associated with increased resistance of colorectal cells against radiation and 5-FU. Down-regulated upon siomycin A, a thiazole antibiotic, treatment, leading to inhibit tumor growth in vivo. {ECO:0000269\|PubMed:21558073, ECO:0000269\|PubMed:21806965}.
Domain:		The KA1 domain mediates binding to phospholipids and targeting to membranes. {ECO:0000250}.
Ptm:		Autophosphorylated: autophosphorylation of the T-loop at Thr-167 and Ser-171 is required for activation. Thr-478 phosphorylation during mitosis promotes interaction with PPP1R8 (Probable). {ECO:0000305\|PubMed:14699119, ECO:0000305\|PubMed:14976552, ECO:0000305\|PubMed:16216881, ECO:0000305\|PubMed:16628004, ECO:0000305\|PubMed:20420823}.
Disease:		Note=Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor- initiating cells and proliferation via its function in cell proliferation regulation.
Miscellaneous:		Potential therapeutic target for treatment of somatic tumors, such as brain and breast cancers, down-regulation of MELK inhibiting tumorigenesis (PubMed:17960622, PubMed:20861186). {ECO:0000305\|PubMed:17960622, ECO:0000305\|PubMed:20861186}.
Similarity:		Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily. {ECO:0000305}.
Sequence caution:		Sequence=BAA11492.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};