| MOB1, comprising the closely related human paralogs MOB1A and MOB1B, is a conserved kinase-activator protein that functions as a central adaptor in the Hippo tumor suppressor pathway and NDR/LATS kinase signaling, linking upstream MST/Hippo kinases to downstream regulators of cell proliferation, apoptosis, differentiation and cytokinesis. The protein adopts a compact MOB fold that binds the N‑terminal regulatory region of NDR and LATS family Ser/Thr kinases and contains several threonine residues that are phosphorylated by MST1/2, creating phospho‑dependent docking surfaces that strengthen MOB1–kinase interactions and stabilize active kinase conformations. Direct binding of human MOB1 to NDR kinases releases an autoinhibitory sequence in NDR, promotes phosphorylation of key regulatory sites in the activation segment and hydrophobic motif, and thereby converts NDR into a catalytically active state, establishing MOB1 as a bona fide kinase-activating subunit rather than a passive scaffold. In the canonical Hippo cascade, MOB1 associates with MST1/2 and coactivates LATS1/2, which phosphorylate and inhibit the transcriptional coactivators YAP and TAZ; loss of Mob1a/b in mouse keratinocytes reduces LATS activity, activates YAP1, and produces hyperproliferative, apoptosis-resistant keratinocyte progenitors with impaired contact inhibition and enhanced self‑renewal, demonstrating that MOB1 restrains tissue growth by enforcing Hippo-dependent control of YAP/TAZ. Mob1a/1b double-mutant mice exhibit embryonic lethality unless at least one wild-type allele is present, and conditional loss of the remaining allele drives trichilemmal carcinoma–like tumors with YAP1 activation, while some human trichilemmal carcinomas show MOB1A/B inactivation together with YAP1 activation, establishing MOB1 as a tumor suppressor whose dosage and integrity are critical for skin homeostasis and cancer susceptibility. In the lung, a MOB1–YAP1/TAZ–NKX2.1 axis controls bronchioalveolar epithelial differentiation, adhesion and tumor formation: inducible deletion of Mob1a/b in bronchioalveolar epithelium produces proliferative but poorly differentiated alveolar cells with reduced surfactant production and respiratory distress features, and reduces urethane-induced lung adenocarcinoma formation by depleting bronchioalveolar stem cells and lowering collagen XVII expression, indicating that MOB1 coordinates Hippo output and hemidesmosome components to maintain stem cell niches and tissue integrity. Beyond growth control, human MOB1A/B contribute to mitotic exit and cytokinesis by regulating midbody microtubule stability and centriole behavior; RNAi-mediated depletion of MOB1A/B causes abscission failure with hyperstable midbody microtubules, increased post-cytokinesis cell motility and prolonged centriole separation, whereas MOB1 overexpression prevents centrosome splitting, showing that MOB1 tunes microtubule dynamics at the intercellular bridge and centriole re-joining after telophase. At the signaling-network level, phospho‑MOB1 integrates inputs from MST/Hippo kinases and relays them to multiple NDR/LATS family members, allowing upstream stress, polarity and mechanical cues to be translated into coordinated changes in proliferation, apoptosis and cytoskeletal architecture. |
