ALK tyrosine kinase receptor (also known as anaplastic lymphoma kinase, ALK) is a neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system [].ALK transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1 [, , ]. ALK acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation [, ]. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction [].
This entry includes ALK and LTK ligand 1 and 2 (ALKL1/2, also known as FAM150A and FAM150B, respectively) from vertebrates. ALKL1/2 are activating ligands for the receptor anaplastic lymphoma kinase (ALK) and the receptor leukocyte tyrosine kinase (LTK) [, ]. However, ALKL1 does not act as a potent physiological ligand for ALK, in contrast to ALKL2 [, ]. Monomeric ALKAL1 binds to LTK, leading to LTK homodimerization and activation [, ]. It is not yet clear if ALKL2 activates ALK as a homodimer or a monomer [, ].
This entry contains Nuclear-interacting partner of ALK (NIPA) and NIPA like proteins, as well as mRNA export factor Rsm1, all of which contain a C3HC-type zinc finger. The domain represented in this entry is found C-terminal to the zinc-finger like domain . Rsm1 is involved in mRNA export from the nucleus []. NIPA is an essential component of an SCF-type E3 ligase complex, SCF(NIPA), a complex that controls mitotic entry by mediating ubiquitination and subsequent degradation of cyclin B1 (CCNB1). Its cell-cycle-dependent phosphorylation regulates the assembly of the SCF(NIPA) complex, restricting CCNB1 ubiquitination activity to interphase. Its inactivation results in nuclear accumulation of CCNB1 in interphase and premature mitotic entry [].
