MOB2

MOB2 is a conserved NDR (nuclear Dbf2-related) kinase-associated protein that couples NDR-family kinase signaling to cell polarity, cytoskeletal organization, and cell-fate decisions across fungi, invertebrates, and mammals (PMID:11747810, PMID:20624913, PMID:23979583). In human cells, hMOB2 binds the N-terminal region of NDR1 in an unphosphorylated state and competes with the activating cofactors hMOB1A/B, thereby acting as a negative regulator of NDR kinase activity in death-receptor signaling and centrosome duplication (PMID:20624913). The activity of Mob2 itself is gated by CDK-dependent phosphorylation, establishing a regulatory layer above the NDR kinase it activates (PMID:21593210). In yeast, the Cbk1–Mob2 module drives asymmetric daughter-cell fate by directing nuclear accumulation of the Ace2 transcription factor (PMID:11747810), and operates in parallel to Ras/PKA signaling (PMID:14871942). In metazoan neurons, Mob2 controls cytoskeletal remodeling and cilia positioning: it promotes neurite outgrowth with altered phospho-Moesin levels (PMID:21237165), regulates Tricornered-dependent neuromuscular junction growth (PMID:23979583), and is required for cortical neuronal migration through control of cilia positioning and Filamin A phosphorylation, with loss-of-function MOB2 variants identified in periventricular nodular heterotopia (PMID:29593499). In disease and injury contexts MOB2 modulates cell migration and phenotypic state by acting on FAK/Akt and cAMP/PKA signaling in glioblastoma (PMID:32286266) and PI3K–AKT signaling in reactive astrocytes (PMID:39863205), and its depletion sensitizes lung cancer cells to PARP inhibitors via p53-dependent DNA damage signaling (PMID:41899447).

1. 2001 High

   Established the founding mechanistic role of the Mob2 module: how a cell generates asymmetric daughter-specific gene expression, by showing Cbk1–Mob2 directs Ace2 transcription factor activation and nuclear localization specifically to the daughter nucleus.

   Evidence Genetic epistasis, localization, and transcriptional reporter assays in S. cerevisiae

   PMID:11747810

   Open questions at the time

   • Does not define the biochemical basis of Mob2–Cbk1 activation of Ace2
   • No structural detail of the Mob2–kinase interaction
2. 2004 Medium

   Resolved whether Mob2/Cbk1 acts within or alongside Ras/PKA in cell cycle and bud-site control, showing it functions as a separate, Ace2-independent pathway.

   Evidence Double-mutant epistasis and overexpression suppression in yeast

   PMID:14871942

   Open questions at the time

   • Molecular targets of the Ace2-independent Mob2/Cbk1 function not identified
   • Single-organism genetic inference only
3. 2009 Medium

   Addressed where Mob2 acts in polarized cells, linking its apical/rhabdomere localization to membrane and cytoskeletal protein positioning during photoreceptor morphogenesis.

   Evidence Immunocytochemistry and RNAi knockdown in Drosophila eye development

   PMID:19834743

   Open questions at the time

   • Direct kinase partner at the rhabdomere not established
   • Mechanism linking Mob2 to Moesin/Crumbs localization unknown
4. 2010 High

   Defined the core biochemical role of human MOB2, showing it binds unphosphorylated NDR1, competes with the activator hMOB1A, and thereby negatively regulates NDR kinase activity — distinguishing it from the activating MOB1 cofactors.

   Evidence Co-immunoprecipitation, RNAi with kinase activity assays, and overexpression functional assays in human cells

   PMID:20624913

   Open questions at the time

   • Structural basis of competitive binding not resolved
   • Whether MOB2 has any positive NDR-independent functions not addressed
5. 2011 High

   Identified an upstream control layer on the Mob2 module, showing CDK (Cdc28) phosphorylates Mob2 at four consensus sites to drive hyphal morphogenesis and polarisome maintenance.

   Evidence Phosphosite mutagenesis, phosphorylation assays, and localization in Candida albicans

   PMID:21593210

   Open questions at the time

   • Whether mammalian MOB2 is similarly CDK-regulated not tested
   • Downstream effectors of phosphorylated Mob2 not fully mapped
6. 2011 Medium

   Extended Mob2 function to metazoan neuronal cytoskeletal remodeling, showing it promotes neurite formation with concomitant changes in actin organization and phospho-Moesin.

   Evidence RNAi knockdown, overexpression, and phospho-Moesin immunostaining in Neuro2A cells

   PMID:21237165

   Open questions at the time

   • No direct kinase pathway placement
   • Relationship to NDR regulatory activity not tested
7. 2013 Medium

   Pinpointed kinase specificity for Mob2 at the synapse, showing it acts dose-dependently with Tricornered (not Warts) NDR kinase to control neuromuscular junction growth.

   Evidence Genetic interaction, rescue, and presynaptic-specific expression in Drosophila

   PMID:23979583

   Open questions at the time

   • Biochemical mode of Mob2–Tricornered interaction not defined
   • Downstream synaptic effectors unidentified
8. 2018 Medium

   Linked MOB2 to mammalian brain development and human disease, showing it is required for cortical neuronal migration via cilia positioning and Filamin A phosphorylation, with loss-of-function variants in periventricular nodular heterotopia.

   Evidence In utero electroporation knockdown, immunostaining, turnover assays, and patient variant characterization in mouse

   PMID:29593499

   Open questions at the time

   • Direct kinase mediating Filamin A phosphorylation not established
   • Genotype-phenotype link based on limited patient data
9. 2020 Medium

   Defined a cancer-context signaling role, showing MOB2 promotes cAMP/PKA signaling and negatively regulates FAK/Akt to suppress glioblastoma migration and invasion.

   Evidence Co-IP, knockdown/overexpression, pharmacological modulation, and xenograft/CAM models

   PMID:32286266

   Open questions at the time

   • Direct PKA-MOB2 binding interface not mapped
   • Connection between this role and NDR kinase regulation unclear
10. 2025 Medium

    Showed MOB2 governs reactive astrocyte phenotypic switching after injury by driving PI3K-AKT activation to promote the A1-to-A2 conversion.

    Evidence Conditional knockout mice, primary astrocyte model, and AKT-activator rescue in a spinal cord injury model

    PMID:39863205

    Open questions at the time

    • Mechanism by which MOB2 activates PI3K-AKT not defined
    • Whether NDR kinases participate in astrocyte switching untested
11. 2026 Medium

    Connected MOB2 to DNA damage and therapeutic vulnerability, showing its depletion sensitizes lung cancer cells to PARP inhibitors through p53-dependent damage signaling and apoptosis.

    Evidence siRNA knockdown, clonogenic/comet/caspase assays, and p53 reconstitution in lung cancer cells

    PMID:41899447

    Open questions at the time

    • Mechanism linking MOB2 to p53 signaling not defined
    • Whether effect requires NDR kinase activity unknown

• How MOB2's biochemical role as a negative NDR kinase regulator mechanistically connects to its diverse in vivo functions in cilia positioning, cytoskeletal remodeling, PKA/AKT signaling, and p53-dependent DNA damage responses remains unresolved.
• No unifying biochemical pathway linking NDR regulation to the cilia/cytoskeletal and PKA/AKT/p53 phenotypes
• No structural model of human MOB2 complexes
• Direct substrates downstream of MOB2-regulated kinases not catalogued in mammals