Introduction
This gene encodes a member of a small family of secreted growth factors that binds heparin and responds to retinoic acid. The encoded protein promotes cell growth, migration, and angiogenesis, in particular during tumorigenesis. This gene has been targeted as a therapeutic for a variety of different disorders. Alternatively spliced transcript variants encoding multiple isoforms have been observed.
Function
Secreted protein that functions as cytokine and growth factor and mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors (PubMed:18469519, PubMed:12573468, PubMed:12122009, PubMed:10212223, PubMed:24458438, PubMed:15466886, PubMed:12084985, PubMed:10772929).
Binds cell-surface proteoglycan receptors via their chondroitin sulfate (CS) groups (PubMed:12084985, PubMed:10212223).
Thereby regulates many processes like inflammatory response, cell proliferation, cell adhesion, cell growth, cell survival, tissue regeneration, cell differentiation and cell migration (PubMed:12573468, PubMed:12122009, PubMed:10212223, PubMed:10683378, PubMed:24458438, PubMed:22323540, PubMed:12084985, PubMed:15466886, PubMed:10772929).
Participates in inflammatory processes by exerting two different activities. Firstly, mediates neutrophils and macrophages recruitment to the sites of inflammation both by direct action by cooperating namely with ITGB2 via LRP1 and by inducing chemokine expression (PubMed:10683378, PubMed:24458438).
This inflammation can be accompanied by epithelial cell survival and smooth muscle cell migration after renal and vessel damage, respectively (PubMed:10683378).
Secondly, suppresses the development of tolerogenic dendric cells thereby inhibiting the differentiation of regulatory T cells and also promote T cell expansion through NFAT signaling and Th1 cell differentiation (PubMed:22323540).
Promotes tissue regeneration after injury or trauma. After heart damage negatively regulates the recruitment of inflammatory cells and mediates cell survival through activation of anti-apoptotic signaling pathways via MAPKs and AKT pathways through the activation of angiogenesis (By similarity).
Also facilitates liver regeneration as well as bone repair by recruiting macrophage at trauma site and by promoting cartilage development by facilitating chondrocyte differentiation (By similarity).
Plays a role in brain by promoting neural precursor cells survival and growth through interaction with heparan sulfate proteoglycans (By similarity).
Binds PTPRZ1 and promotes neuronal migration and embryonic neurons survival (PubMed:10212223).
Binds SDC3 or GPC2 and mediates neurite outgrowth and cell adhesion (PubMed:12084985, PubMed:1768439).
Binds chondroitin sulfate E and heparin leading to inhibition of neuronal cell adhesion induced by binding with GPC2 (PubMed:12084985).
Binds CSPG5 and promotes elongation of oligodendroglial precursor-like cells (By similarity).
Also binds ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth (PubMed:15466886, PubMed:1768439).
Binds LRP1; promotes neuronal survival (PubMed:10772929).
Binds ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886).
Binds anaplastic lymphoma kinase (ALK) which induces ALK activation and subsequent phosphorylation of the insulin receptor substrate (IRS1), followed by the activation of mitogen-activated protein kinase (MAPK) and PI3-kinase, and the induction of cell proliferation (PubMed:12122009).
Promotes epithelial to mesenchymal transition through interaction with NOTCH2 (PubMed:18469519).
During arteriogenesis, plays a role in vascular endothelial cell proliferation by inducing VEGFA expression and release which in turn induces nitric oxide synthase expression. Moreover activates vasodilation through nitric oxide synthase activation (By similarity).
Negatively regulates bone formation in response to mechanical load by inhibiting Wnt/beta-catenin signaling in osteoblasts (By similarity).
In addition plays a role in hippocampal development, working memory, auditory response, early fetal adrenal gland development and the female reproductive system (By similarity).
Biological Process
Adrenal gland development Source: UniProtKB
Behavioral fear response Source: Ensembl
Cell differentiation Source: UniProtKB
Cerebellar granular layer development Source: Ensembl
Cerebral cortex development Source: Ensembl
Cytoskeleton organization Source: UniProtKB
Defecation Source: Ensembl
Dentate gyrus development Source: Ensembl
Estrous cycle Source: UniProtKB
Glial cell projection elongation Source: UniProtKB
Leukocyte chemotaxis involved in inflammatory response Source: UniProtKB
Negative regulation of canonical Wnt signaling pathway Source: UniProtKB
Negative regulation of cardiac muscle cell apoptotic process Source: UniProtKB
Negative regulation of cell adhesion Source: UniProtKB
Negative regulation of epithelial cell apoptotic process Source: UniProtKB
Negative regulation of inflammatory response to wounding Source: UniProtKB
Negative regulation of neuron apoptotic process Source: UniProtKB
Negative regulation of ossification Source: UniProtKB
Negative regulation of regulatory T cell differentiation Source: UniProtKB
Nervous system development Source: UniProtKB
Oogenesis Source: UniProtKB
Positive regulation of artery morphogenesis Source: UniProtKB
Positive regulation of blood vessel branching Source: UniProtKB
Positive regulation of cartilage development Source: UniProtKB
Positive regulation of cell adhesion Source: UniProtKB
Positive regulation of cell division Source: UniProtKB-KW
Positive regulation of cell migration Source: UniProtKB
Positive regulation of epithelial to mesenchymal transition Source: UniProtKB
Positive regulation of hepatocyte proliferation Source: UniProtKB
Positive regulation of inflammatory response Source: UniProtKB
Positive regulation of inflammatory response to wounding Source: UniProtKB
Positive regulation of interleukin-12 production Source: UniProtKB
Positive regulation of keratinocyte proliferation Source: UniProtKB
Positive regulation of leukocyte adhesion to vascular endothelial cell Source: UniProtKB
Positive regulation of leukocyte cell-cell adhesion Source: UniProtKB
Positive regulation of leukocyte chemotaxis Source: UniProtKB
Positive regulation of macrophage chemotaxis Source: UniProtKB
Positive regulation of neural precursor cell proliferation Source: UniProtKB
Positive regulation of neuron migration Source: UniProtKB
Positive regulation of neuron projection development Source: UniProtKB
Positive regulation of neutrophil chemotaxis Source: UniProtKB
Positive regulation of neutrophil extravasation Source: UniProtKB
Positive regulation of oligodendrocyte differentiation Source: UniProtKB
Positive regulation of smooth muscle cell chemotaxis Source: UniProtKB
Positive regulation of substrate adhesion-dependent cell spreading Source: UniProtKB
Positive regulation of T cell differentiation Source: UniProtKB
Positive regulation of transcription, DNA-templated Source: Ensembl
Positive regulation of vascular endothelial cell proliferation Source: UniProtKB
Regulation of actin cytoskeleton reorganization Source: UniProtKB
Regulation of behavior Source: Ensembl
Regulation of bone remodeling Source: UniProtKB
Regulation of chondrocyte differentiation Source: UniProtKB
Response to auditory stimulus Source: UniProtKB
Response to glucocorticoid Source: Ensembl
Response to wounding Source: UniProtKB
Response to xenobiotic stimulus Source: Ensembl
Short-term memory Source: Ensembl
Signal transduction Source: ProtInc
T cell activation involved in immune response Source: UniProtKB
Tissue regeneration Source: UniProtKB
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