Microtubule‐associated serine/threonine kinase (MAST)

Microtubule-associated serine/threonine (MAST) kinases are evolutionarily conserved modular proteins in the AGC protein kinase superfamily, characterized by: an N-terminal DUF1908 domain; a central serine/threonine kinase domain; and a C-terminal PDZ domain. MAST has four isoforms (MAST1-4) in mammals, which are widely expressed in tissues such as brain, heart, and liver^[1].
MAST kinases can phosphorylate multiple substrates: MAST2 phosphorylates PTEN (reducing its activity/stability, interacting through the PDZ domain), NHE3 (inhibiting ion transport), and TRAF6 (regulating NF-κB signaling); MAST3 phosphorylates ARPP-16 (serine 46, inhibiting PP2A activity in striatal neurons); MAST4 phosphorylates Sox9 (serine 494, targeting proteasomal degradation) and ERM (serine 367, enhancing transcription). Among them, MAST1 can interact with proteins such as β2-syntrophin (linking the dystrophin complex and microtubules), and MAST2 with PCLKC (tumor suppressor) or/and 14-3-3 (phosphorylation-dependent interaction)^[1].
Mechanistically, their domains enable substrate recognition (e.g., PDZ domain binding to C-terminal motif) and regulatory input (e.g., dimerization via PDZ domain). MAST kinases participate in pathways such as PI3K/mTOR (MAST4-PTEN axis in myeloma), ERK/MAPK (MAST1-cRaf/MEK complex in cisplatin resistance), and NF-κB (MAST2 inhibits TRAF6-dependent activation, MAST3 enhances TLR4-dependent activation in IBD)^[1].
MAST kinases are closely associated with human diseases, including: cancer (MAST1/2 fusion/overexpression in breast/liver cancer, MAST4 in myeloma), neuronal diseases (rabies virus disrupts MAST2-PTEN interaction, MAST1 mutations lead to intellectual disability), cystic fibrosis (MAST2 regulates CFTR surface levels), male infertility (MAST2 duplication in azoospermia, MAST4 in spermatogonial stem cells), and inflammation (MAST3 in inflammatory bowel disease, MAST2 in LPS-induced inflammatory response). The modular structure and diverse interactions of MAST kinases make them key targets for understanding disease mechanisms^[1].

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