UniProt functional annotation for Q99828



	UniProt functional annotation for Q99828

UniProt code: Q99828.

Organism: Homo sapiens (Human).

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

Function: Calcium-binding protein that plays a role in the regulation of numerous cellular processes, such as cell differentiation, cell division, cell proliferation, cell migration, thrombosis, angiogenesis, cardiac hypertrophy and apoptosis. Involved in bone marrow megakaryocyte differentiation by negatively regulating thrombopoietin- mediated signaling pathway. Participates in the endomitotic cell cycle of megakaryocyte, a form of mitosis in which both karyokinesis and cytokinesis are interrupted. Plays a role in integrin signaling by negatively regulating alpha-IIb/beta3 activation in thrombin-stimulated megakaryocytes preventing platelet aggregation. Up-regulates PTK2/FAK1 activity, and is also needed for the recruitment of PTK2/FAK1 to focal adhesions; it thus appears to play an important role in focal adhesion formation. Positively regulates cell migration on fibronectin in a CDC42-dependent manner, the effect being negatively regulated by PAK1. Functions as a negative regulator of stress activated MAP kinase (MAPK) signaling pathways. Down-regulates inositol 1,4,5-trisphosphate receptor-dependent calcium signaling. Involved in sphingosine kinase SPHK1 translocation to the plasma membrane in a N-myristoylation- dependent manner preventing TNF-alpha-induced apoptosis. Regulates serine/threonine-protein kinase PLK3 activity for proper completion of cell division progression. Plays a role in microtubule (MT) dynamics during neuronal development; disrupts the MT depolymerization activity of STMN2 attenuating NGF-induced neurite outgrowth and the MT reorganization at the edge of lamellipodia. Promotes cardiomyocyte hypertrophy via activation of the calcineurin/NFAT signaling pathway. Stimulates calcineurin PPP3R1 activity by mediating its anchoring to the sarcolemma. In ischemia-induced (pathological or adaptive) angiogenesis, stimulates endothelial cell proliferation, migration and microvessel formation by activating the PAK1 and ERK1/ERK2 signaling pathway. Promotes also cancer cell survival and proliferation. May regulate cell cycle and differentiation of spermatogenic germ cells, and/or differentiation of supporting Sertoli cells.

Function: [Isoform 2]: Plays a regulatory role in angiogenesis and tumor growth by mediating PKD/PRKD2-induced vascular endothelial growth factor A (VEGFA) secretion. {ECO:0000269|PubMed:23503467}.

Function: (Microbial infection) Involved in keratinocyte-intrinsic immunity to human beta-papillomaviruses (HPVs). {ECO:0000269|PubMed:30068544}.

Subunit: Monomer. Interacts with MYO1C. Interacts (via C-terminal region) with PPP3R1 and CACNA1C; the interactions increase upon cardiomyocytes hypertrophy (By similarity). Interacts with the heterodimeric integrin alpha-IIb/beta3 (ITGA2B-ITGB3). Interacts with ITGA2B (via cytoplasmic domain); the interaction is direct and calcium- dependent. Interacts with the protein kinases PLK2/SNK and PRKDC (via the region immediately upstream of the kinase domain). Interacts with PLK3; the interaction inhibits PLK3 kinase activity. Interacts with PSEN2. Interacts (via C-terminus) with F8. Interacts with NBR1 (via C- terminus). Interacts with FEZ1 (via C-terminus). Interacts with UBR5 (via C-terminus); the interaction is sensitive to DNA damage, and may target CIB1 for ubiquitin-mediated degradation. Interacts with IFI6; the interaction is direct (PubMed:15685448). Interacts with BCL2 (PubMed:15685448). Interacts with ITPR3; the interaction occurs in a calcium-dependent manner. Interacts with PTK2/FAK1. Interacts with MAP3K5; the interaction inhibits MAP3K5 activation by phosphorylation, and its subsequent interaction with TRAF2. Isoform 2 interacts with PRKD2 (via N-terminal AP-rich region), PTK2/FAK1 and PAK1. Interacts with TAS1R2 (via C-terminus); the interaction is independent of the myristoylation state of CIB1. Interacts (via C-terminal region) with STMN2 (via the N-terminal region); the interaction is direct, occurs in a calcium-dependent manner and attenuates the STMN2-induced neurite outgrowth inhibition. Interacts with SPHK1, the interaction occurs in a calcium-dependent manner. Interacts with ITGA2B (via C-terminal cytoplasmic tail); the interaction occurs upon platelet aggregation and is stabilized/increased in a calcium and magnesium-dependent manner. Interacts with PAK1 (via N-terminal region); the interaction is direct and occurs in a calcium-dependent manner. Interacts with RAC3 (via C- terminal region); the interaction induces their association with the cytoskeleton upon alpha-IIb/beta3 integrin-mediated adhesion. Interacts with ITGA5 and ITGAV. Interacts and forms a complex with TMC6 and TMC8 (PubMed:30068544). {ECO:0000250, ECO:0000269|PubMed:10366599, ECO:0000269|PubMed:10477286, ECO:0000269|PubMed:11323029, ECO:0000269|PubMed:11756406, ECO:0000269|PubMed:11856312, ECO:0000269|PubMed:12011095, ECO:0000269|PubMed:12023286, ECO:0000269|PubMed:12881299, ECO:0000269|PubMed:14992593, ECO:0000269|PubMed:15475008, ECO:0000269|PubMed:15574431, ECO:0000269|PubMed:15685448, ECO:0000269|PubMed:15883187, ECO:0000269|PubMed:15933764, ECO:0000269|PubMed:16061695, ECO:0000269|PubMed:16418530, ECO:0000269|PubMed:16723353, ECO:0000269|PubMed:18627437, ECO:0000269|PubMed:19388079, ECO:0000269|PubMed:19805025, ECO:0000269|PubMed:19854831, ECO:0000269|PubMed:20473878, ECO:0000269|PubMed:20951827, ECO:0000269|PubMed:21215777, ECO:0000269|PubMed:21264284, ECO:0000269|PubMed:21388953, ECO:0000269|PubMed:22283712, ECO:0000269|PubMed:22779914, ECO:0000269|PubMed:23503467, ECO:0000269|PubMed:24011356, ECO:0000269|PubMed:30068544, ECO:0000269|PubMed:9030514, ECO:0000269|PubMed:9372844}.

Subunit: (Microbial infection) Interacts with human papillomavirus 4/HPV4 protein E8, human papillomavirus 5/HPV5 protein E1, and human papillomavirus 16/HPV16 proteins E2 and E5. {ECO:0000269|PubMed:30068544}.

Subcellular location: Membrane; Lipid-anchor. Cell membrane, sarcolemma. Cell membrane. Apical cell membrane. Cell projection, ruffle membrane. Cell projection, filopodium tip. Cell projection, growth cone {ECO:0000269|PubMed:21215777}. Cell projection, lamellipodium {ECO:0000269|PubMed:21215777}. Cytoplasm. Cytoplasm, cytoskeleton. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Cytoplasm, perinuclear region. Nucleus {ECO:0000269|PubMed:30068544}. Cell projection, neuron projection {ECO:0000269|PubMed:21215777}. Perikaryon {ECO:0000269|PubMed:21215777}. Note=Colocalized with PPP3R1 at the cell membrane of cardiomyocytes in the hypertrophic heart (By similarity). Colocalized with NBR1 to the perinuclear region. Colocalizes with TAS1R2 in apical regions of taste receptor cells. Colocalized with RAC3 in the perinuclear area and at the cell periphery. Colocalized with PAK1 within membrane ruffles during cell spreading upon readhesion to fibronectin. Redistributed to the cytoskeleton upon platelet aggregation. Translocates from the cytosol to the plasma membrane in a calcium-dependent manner. Colocalized with PLK3 at centrosomes in ductal breast carcinoma cells. {ECO:0000250}.

Subcellular location: [Isoform 2]: Cytoplasm, perinuclear region {ECO:0000269|PubMed:23503467}. Golgi apparatus, trans-Golgi network {ECO:0000269|PubMed:23503467}.

Tissue specificity: Ubiquitously expressed. Expressed in the epidermis, hair follicles and keratinocytes (PubMed:30068544). Detected in platelets and in cell lines of megakaryocytic and erythrocytic lineages. Both isoform 1 and isoform 2 are detected in various cancer cell lines, with isoform 2 being the predominant form (at protein level). {ECO:0000269|PubMed:10477286, ECO:0000269|PubMed:11856312, ECO:0000269|PubMed:23503467, ECO:0000269|PubMed:30068544, ECO:0000269|PubMed:9030514, ECO:0000269|PubMed:9372844}.

Induction: Up-regulated during breast cancer progression.

Domain: The EF-hands may also bind magnesium ions in the presence of high Mg(2+) levels and low Ca(2+) levels.

Ptm: Phosphorylation of isoform 2 at Ser-118 by PRKD2 increases its ability to stimulate tumor angiogenesis. {ECO:0000305|PubMed:23503467}.

Disease: Epidermodysplasia verruciformis 3 (EV3) [MIM:618267]: A form of epidermodysplasia verruciformis, a rare genodermatosis associated with a high risk of skin carcinoma that results from an abnormal susceptibility to infection by specific human papillomaviruses, including the oncogenic HPV5. Infection leads to the early development of disseminated flat wart-like and pityriasis versicolor-like skin lesions. Cutaneous Bowen's carcinomas in situ and invasive squamous cell carcinomas develop in about half of the patients, mainly on sun- exposed skin areas. EV3 inheritance is autosomal recessive. {ECO:0000269|PubMed:30068544}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: The binding of either calcium or magnesium significantly increases the structural stability of the protein in comparison to apo- CIB (calcium- and magnesium-free form). {ECO:0000305|PubMed:14992593}.

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:		Calcium-binding protein that plays a role in the regulation of numerous cellular processes, such as cell differentiation, cell division, cell proliferation, cell migration, thrombosis, angiogenesis, cardiac hypertrophy and apoptosis. Involved in bone marrow megakaryocyte differentiation by negatively regulating thrombopoietin- mediated signaling pathway. Participates in the endomitotic cell cycle of megakaryocyte, a form of mitosis in which both karyokinesis and cytokinesis are interrupted. Plays a role in integrin signaling by negatively regulating alpha-IIb/beta3 activation in thrombin-stimulated megakaryocytes preventing platelet aggregation. Up-regulates PTK2/FAK1 activity, and is also needed for the recruitment of PTK2/FAK1 to focal adhesions; it thus appears to play an important role in focal adhesion formation. Positively regulates cell migration on fibronectin in a CDC42-dependent manner, the effect being negatively regulated by PAK1. Functions as a negative regulator of stress activated MAP kinase (MAPK) signaling pathways. Down-regulates inositol 1,4,5-trisphosphate receptor-dependent calcium signaling. Involved in sphingosine kinase SPHK1 translocation to the plasma membrane in a N-myristoylation- dependent manner preventing TNF-alpha-induced apoptosis. Regulates serine/threonine-protein kinase PLK3 activity for proper completion of cell division progression. Plays a role in microtubule (MT) dynamics during neuronal development; disrupts the MT depolymerization activity of STMN2 attenuating NGF-induced neurite outgrowth and the MT reorganization at the edge of lamellipodia. Promotes cardiomyocyte hypertrophy via activation of the calcineurin/NFAT signaling pathway. Stimulates calcineurin PPP3R1 activity by mediating its anchoring to the sarcolemma. In ischemia-induced (pathological or adaptive) angiogenesis, stimulates endothelial cell proliferation, migration and microvessel formation by activating the PAK1 and ERK1/ERK2 signaling pathway. Promotes also cancer cell survival and proliferation. May regulate cell cycle and differentiation of spermatogenic germ cells, and/or differentiation of supporting Sertoli cells.



Function:		[Isoform 2]: Plays a regulatory role in angiogenesis and tumor growth by mediating PKD/PRKD2-induced vascular endothelial growth factor A (VEGFA) secretion. {ECO:0000269\|PubMed:23503467}.



Function:		(Microbial infection) Involved in keratinocyte-intrinsic immunity to human beta-papillomaviruses (HPVs). {ECO:0000269\|PubMed:30068544}.


Subunit:		Monomer. Interacts with MYO1C. Interacts (via C-terminal region) with PPP3R1 and CACNA1C; the interactions increase upon cardiomyocytes hypertrophy (By similarity). Interacts with the heterodimeric integrin alpha-IIb/beta3 (ITGA2B-ITGB3). Interacts with ITGA2B (via cytoplasmic domain); the interaction is direct and calcium- dependent. Interacts with the protein kinases PLK2/SNK and PRKDC (via the region immediately upstream of the kinase domain). Interacts with PLK3; the interaction inhibits PLK3 kinase activity. Interacts with PSEN2. Interacts (via C-terminus) with F8. Interacts with NBR1 (via C- terminus). Interacts with FEZ1 (via C-terminus). Interacts with UBR5 (via C-terminus); the interaction is sensitive to DNA damage, and may target CIB1 for ubiquitin-mediated degradation. Interacts with IFI6; the interaction is direct (PubMed:15685448). Interacts with BCL2 (PubMed:15685448). Interacts with ITPR3; the interaction occurs in a calcium-dependent manner. Interacts with PTK2/FAK1. Interacts with MAP3K5; the interaction inhibits MAP3K5 activation by phosphorylation, and its subsequent interaction with TRAF2. Isoform 2 interacts with PRKD2 (via N-terminal AP-rich region), PTK2/FAK1 and PAK1. Interacts with TAS1R2 (via C-terminus); the interaction is independent of the myristoylation state of CIB1. Interacts (via C-terminal region) with STMN2 (via the N-terminal region); the interaction is direct, occurs in a calcium-dependent manner and attenuates the STMN2-induced neurite outgrowth inhibition. Interacts with SPHK1, the interaction occurs in a calcium-dependent manner. Interacts with ITGA2B (via C-terminal cytoplasmic tail); the interaction occurs upon platelet aggregation and is stabilized/increased in a calcium and magnesium-dependent manner. Interacts with PAK1 (via N-terminal region); the interaction is direct and occurs in a calcium-dependent manner. Interacts with RAC3 (via C- terminal region); the interaction induces their association with the cytoskeleton upon alpha-IIb/beta3 integrin-mediated adhesion. Interacts with ITGA5 and ITGAV. Interacts and forms a complex with TMC6 and TMC8 (PubMed:30068544). {ECO:0000250, ECO:0000269\|PubMed:10366599, ECO:0000269\|PubMed:10477286, ECO:0000269\|PubMed:11323029, ECO:0000269\|PubMed:11756406, ECO:0000269\|PubMed:11856312, ECO:0000269\|PubMed:12011095, ECO:0000269\|PubMed:12023286, ECO:0000269\|PubMed:12881299, ECO:0000269\|PubMed:14992593, ECO:0000269\|PubMed:15475008, ECO:0000269\|PubMed:15574431, ECO:0000269\|PubMed:15685448, ECO:0000269\|PubMed:15883187, ECO:0000269\|PubMed:15933764, ECO:0000269\|PubMed:16061695, ECO:0000269\|PubMed:16418530, ECO:0000269\|PubMed:16723353, ECO:0000269\|PubMed:18627437, ECO:0000269\|PubMed:19388079, ECO:0000269\|PubMed:19805025, ECO:0000269\|PubMed:19854831, ECO:0000269\|PubMed:20473878, ECO:0000269\|PubMed:20951827, ECO:0000269\|PubMed:21215777, ECO:0000269\|PubMed:21264284, ECO:0000269\|PubMed:21388953, ECO:0000269\|PubMed:22283712, ECO:0000269\|PubMed:22779914, ECO:0000269\|PubMed:23503467, ECO:0000269\|PubMed:24011356, ECO:0000269\|PubMed:30068544, ECO:0000269\|PubMed:9030514, ECO:0000269\|PubMed:9372844}.
Subunit:		(Microbial infection) Interacts with human papillomavirus 4/HPV4 protein E8, human papillomavirus 5/HPV5 protein E1, and human papillomavirus 16/HPV16 proteins E2 and E5. {ECO:0000269\|PubMed:30068544}.
Subcellular location:		Membrane; Lipid-anchor. Cell membrane, sarcolemma. Cell membrane. Apical cell membrane. Cell projection, ruffle membrane. Cell projection, filopodium tip. Cell projection, growth cone {ECO:0000269\|PubMed:21215777}. Cell projection, lamellipodium {ECO:0000269\|PubMed:21215777}. Cytoplasm. Cytoplasm, cytoskeleton. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Cytoplasm, perinuclear region. Nucleus {ECO:0000269\|PubMed:30068544}. Cell projection, neuron projection {ECO:0000269\|PubMed:21215777}. Perikaryon {ECO:0000269\|PubMed:21215777}. Note=Colocalized with PPP3R1 at the cell membrane of cardiomyocytes in the hypertrophic heart (By similarity). Colocalized with NBR1 to the perinuclear region. Colocalizes with TAS1R2 in apical regions of taste receptor cells. Colocalized with RAC3 in the perinuclear area and at the cell periphery. Colocalized with PAK1 within membrane ruffles during cell spreading upon readhesion to fibronectin. Redistributed to the cytoskeleton upon platelet aggregation. Translocates from the cytosol to the plasma membrane in a calcium-dependent manner. Colocalized with PLK3 at centrosomes in ductal breast carcinoma cells. {ECO:0000250}.
Subcellular location:		[Isoform 2]: Cytoplasm, perinuclear region {ECO:0000269\|PubMed:23503467}. Golgi apparatus, trans-Golgi network {ECO:0000269\|PubMed:23503467}.
Tissue specificity:		Ubiquitously expressed. Expressed in the epidermis, hair follicles and keratinocytes (PubMed:30068544). Detected in platelets and in cell lines of megakaryocytic and erythrocytic lineages. Both isoform 1 and isoform 2 are detected in various cancer cell lines, with isoform 2 being the predominant form (at protein level). {ECO:0000269\|PubMed:10477286, ECO:0000269\|PubMed:11856312, ECO:0000269\|PubMed:23503467, ECO:0000269\|PubMed:30068544, ECO:0000269\|PubMed:9030514, ECO:0000269\|PubMed:9372844}.
Induction:		Up-regulated during breast cancer progression.
Domain:		The EF-hands may also bind magnesium ions in the presence of high Mg(2+) levels and low Ca(2+) levels.
Ptm:		Phosphorylation of isoform 2 at Ser-118 by PRKD2 increases its ability to stimulate tumor angiogenesis. {ECO:0000305\|PubMed:23503467}.
Disease:		Epidermodysplasia verruciformis 3 (EV3) [MIM:618267]: A form of epidermodysplasia verruciformis, a rare genodermatosis associated with a high risk of skin carcinoma that results from an abnormal susceptibility to infection by specific human papillomaviruses, including the oncogenic HPV5. Infection leads to the early development of disseminated flat wart-like and pityriasis versicolor-like skin lesions. Cutaneous Bowen's carcinomas in situ and invasive squamous cell carcinomas develop in about half of the patients, mainly on sun- exposed skin areas. EV3 inheritance is autosomal recessive. {ECO:0000269\|PubMed:30068544}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		The binding of either calcium or magnesium significantly increases the structural stability of the protein in comparison to apo- CIB (calcium- and magnesium-free form). {ECO:0000305\|PubMed:14992593}.