TIMAP, the versatile protein phosphatase 1 regulator in endothelial cells

Abstract

Transforming growth factor (TGF)-β inhibited membrane associated protein, TIMAP, is the member of the myosin phosphatase targeting protein (MYPT) family of protein phosphatase 1 (PP1) regulatory subunits. The N-terminal part of TIMAP has a typical MYPT family structure with a sequence element called MyPhone (myosin phosphatase N-terminal element), a putative bipartite nuclear localization signal, a PP1 catalytic subunit binding motif, and five ankyrin repeats. The C-terminal half of TIMAP is intrinsically disordered, but ends with a functional CAAX box for lipid modification which allows localization of TIMAP at the plasma membrane. TIMAP is prenylated by farnesyl transferase with the contribution of the anchoring protein, RACK1 in the cytoplasm. The controlling effect of TIMAP on PP1 is moderated by PKA/GSK3β and PKC mediated phosphorylation of TIMAP, the sites are located in the disordered region of the protein. TIMAP is abundant in endothelial cells. A growing body of evidence attained through characterization of newly identified protein partners calls attention to its critical role in normal and pathological activities of the endothelium via regulation of PP1. TIMAP binds the non-integrin laminin receptor 1 and the endothelin converting enzyme 1, which may connect TIMAP to angiogenesis, tumor invasion and metastasis. Barrier protecting role of TIMAP was shown for pulmonary artery endothelial cells. ERM (ezrin-radixin-moesin) proteins, as potential in vivo PP1-TIMAP substrates, are critical targets in the barrier maintenance. TIMAP affects phosphorylation level and subcellular localization of merlin and eukaryotic elongation factor-1A1. Merlin is a key component of signaling pathways regulating cell proliferation, membrane domain formation and cell-cell junction organization. Noncanonical functions of the elongation factor include a role in organization of cytoskeleton dynamics and in apoptosis. The interacting/binding partners identified so far demonstrate a rather complex role of TIMAP in key functions of the endothelium offering TIMAP as a plausible target in pathological issues. © 2017 IUBMB Life, 69(12):918–928, 2017.