NISCH
Description
The NISCH (nischarin) is a protein-coding gene located on chromosome 3.
Nischarin is a protein encoded by the NISCH gene in humans. It localizes to the inner layer of the plasma membrane and early and recycling endosome membranes. NISCH is a scaffold protein related to Sorting nexins, regulating protein cargo traffic. The mouse ortholog influences cytoskeletal organization and cell migration by binding to alpha-5-beta-1 integrin. In humans, NISCH binds to insulin receptor substrate 4 (IRS4) to mediate alpha-5 integrin translocation from the cell membrane to endosomes. In cardiac tissue, NISCH affects cell growth and death, while in neural tissue, it affects neuronal growth and differentiation. Reduced expression of NISCH occurs in human breast cancers, and overexpression reduces tumor growth and metastasis, potentially by limiting alpha-5 integrin expression. NISCH interacts with IRS4, Integrin alpha 5, and small GTPases Rac1, Rab4a, Rab9a, Rab14, and Rab38 in GTP-bound form. NISCH also interacts with phospholipid PI(3)P via its PX domain.
NISCH acts as either the functional imidazoline-1 receptor (I1R) candidate or a membrane-associated mediator of I1R signaling. It binds various imidazoline ligands, initiating cell signaling cascades that promote cell survival, growth, and migration. Activating NISCH with the agonist rilmenidine increases phosphorylation of mitogen-activated protein kinases MAPK1 and MAPK3 in rostral ventrolateral medulla (RVLM) neurons, leading to rilmenidine-induced hypotension. Blocking NISCH activation with efaroxan abolishes rilmenidine-induced mitogen-activated protein kinase phosphorylation in RVLM neurons. NISCH modulates Rac-regulated signal transduction pathways, suppressing Rac1-stimulated cell migration by interacting with PAK1 and inhibiting its kinase activity. It also blocks Pak-independent Rac signaling by interacting with RAC1, inhibiting Rac1-stimulated NF-kB response element and cyclin D1 promoter activation. NISCH inhibits LIMK1 kinase activity by reducing LIMK1 'Tyr-508' phosphorylation. It inhibits Rac-induced cell migration and invasion in breast and colon epithelial cells, and inhibits lamellipodia formation when overexpressed. NISCH plays a role in protecting against apoptosis. In association with IRS4, it enhances insulin activation of MAPK1 and MAPK3. When overexpressed, NISCH induces redistribution of cell surface ITGA5 integrin to intracellular endosomal structures.
NISCH is also known as I-1, IR1, IRAS, hIRAS.
