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 [].
Sterile alpha motif (SAM) domains are known to be involved in diverse protein-protein interactions, associating with both SAM-containing and non-SAM-containing proteins pathway []. SAM domains exhibit a conserved structure, consisting of a 4-5-helical bundle of two orthogonally packed alpha-hairpins. However SAM domains display a diversity of function, being involved in interactions with proteins, DNA and RNA []. The name sterile alpha motif arose from its presence in proteins that are essential for yeast sexual differentiation. The SAM domain has had various names, including SPM, PTN (pointed), SEP (yeast sterility, Ets-related, PcG proteins), NCR (N-terminal conserved region) and HLH (helix-loop-helix) domain, all of which are related and can be classified as SAM domains.SAM domains occur in eukaryotic and in some bacterial proteins. Structures have been determined for several proteins that contain SAM domains, including Ets-1 transcription factor, which plays a role in the development and invasion of tumour cells by regulating the expression of matrix-degrading proteases []; Etv6 transcription factor, gene rearrangements of which have been demonstrated in several malignancies []; EphA4 receptor tyrosine kinase, which is believed to be important for the correct localization of a motoneuron pool to a specific position in the spinal cord []; EphB2 receptor, which is involved in spine morphogenesis via intersectin, Cdc42 and N-Wasp []; p73, a p53 homologue involved in neuronal development []; and polyhomeotic, which is a member of the Polycomb group of genes (Pc-G) required for the maintenance of the spatial expression pattern of homeotic genes [].
