INPPL1

INPPL1, also known as SHIP2 (SH2-containing inositol-5'-phosphatase 2), is a protein encoded by the INPPL1 gene in humans. It belongs to the SH2-containing inositol-5'-phosphatase (SHIP) family of enzymes. SHIPs are lipid phosphatases that hydrolyze phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol (3,4)-bisphosphate (PIP2).

Function

The primary function of INPPL1 is the dephosphorylation of PIP3 at the 5' position of the inositol ring. PIP3 is a crucial signaling molecule in the phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in various cellular processes, including cell growth, proliferation, survival, and metabolism. By reducing PIP3 levels, INPPL1 negatively regulates the PI3K signaling pathway.

INPPL1 plays a role in various biological processes, including:

• Insulin signaling: INPPL1 modulates insulin signaling by influencing the levels of PIP3 in insulin-responsive tissues.
• Immune cell regulation: INPPL1 is involved in the regulation of immune cell function, influencing processes such as B cell receptor signaling and mast cell activation.
• Bone remodeling: INPPL1 affects osteoclast function and bone resorption.
• Cancer: INPPL1 is implicated in cancer development and progression, with its role being complex and context-dependent. In some cancers, it acts as a tumor suppressor, while in others, it may promote tumor growth.

Structure

INPPL1 contains several domains, including an SH2 domain, an inositol-5'-phosphatase catalytic domain, and a proline-rich region. The SH2 domain allows INPPL1 to bind to phosphotyrosine residues on activated receptor tyrosine kinases and other signaling molecules, enabling it to be recruited to sites of PIP3 production.

Clinical Significance

Mutations and altered expression of INPPL1 have been linked to various diseases, including:

• Type 2 diabetes: Dysregulation of INPPL1 can contribute to insulin resistance.
• Obesity: INPPL1 may play a role in the development of obesity.
• Cancer: As mentioned above, INPPL1 has been implicated in the pathogenesis of various cancers.
• Spondyloepiphyseal dysplasia tarda (SEDT): Certain mutations in INPPL1 have been identified as causing SEDT, a rare genetic disorder affecting bone and cartilage development.

Interactions

INPPL1 interacts with a variety of proteins involved in signal transduction and cellular regulation. These interactions allow INPPL1 to be recruited to specific cellular locations and to regulate the activity of other signaling pathways.