MOB2

MOB2 is a conserved regulatory scaffold that modulates NDR/LATS-family kinase signaling and multiple downstream pathways controlling cell polarity, morphogenesis, and neuronal positioning. In human cells, MOB2 binds the N-terminal region of NDR1/2 kinases in competition with the activating cofactor MOB1, thereby restraining NDR kinase activity and NDR-dependent processes including centrosome duplication and death receptor signaling (PMID:20624913). Beyond NDR regulation, MOB2 participates in cAMP/PKA-mediated suppression of the FAK/Akt axis to limit glioblastoma cell migration (PMID:32286266), activates PI3K-AKT signaling to promote reactive astrocyte phenotype switching after spinal cord injury (PMID:39863205), and controls cortical neuronal migration through regulation of Filamin A phosphorylation downstream of the protocadherin Dchs1 (PMID:29593499). In budding yeast and Candida, Mob2 partners with the NDR kinase Cbk1 to direct asymmetric daughter-cell gene expression via the Ace2 transcription factor, and CDK-dependent phosphorylation of Mob2 is essential for hyphal morphogenesis (PMID:11747810, PMID:21593210).

1. 2001 High

   Establishing MOB2 as an essential NDR kinase cofactor for asymmetric cell-fate determination resolved how daughter-specific transcription is achieved in yeast: Mob2 and Cbk1 cooperate to activate and localize the Ace2 transcription factor exclusively to the daughter nucleus.

   Evidence Genetic epistasis, localization, and ectopic Ace2 expression in S. cerevisiae

   PMID:11747810

   Open questions at the time

   • Biochemical mechanism by which Mob2 activates Cbk1 kinase was not resolved
   • Whether the Mob2-Cbk1 module has conserved functions in metazoans was unknown
2. 2004 Medium

   Demonstrating that the Mob2/Cbk1 pathway acts in parallel with Ras/PKA signaling for bud site selection expanded MOB2 function beyond Ace2 regulation and established cross-talk with cAMP/PKA signaling.

   Evidence Genetic suppression of mob2Δ by PKA catalytic subunit overexpression in S. cerevisiae

   PMID:14871942

   Open questions at the time

   • Physical or biochemical basis of Mob2-PKA cross-talk was not defined
   • Whether this parallel relationship is conserved in mammalian cells was untested
3. 2009 Medium

   Drosophila Mob2 localization studies in photoreceptors provided the first evidence that MOB2 functions at apical membranes to organize polarity determinants (Crumbs, phospho-Moesin) in a multicellular developmental context.

   Evidence Immunocytochemistry and RNAi knockdown in Drosophila photoreceptors

   PMID:19834743

   Open questions at the time

   • Direct binding partners mediating apical targeting were not identified
   • Whether MOB2 acts through an NDR kinase in this context was not tested
4. 2010 High

   Identification of human MOB2 as a negative regulator of NDR kinases — binding unphosphorylated NDR1 and competing with the activator MOB1 — inverted the expected activating role and established a competitive cofactor-switching mechanism for NDR regulation.

   Evidence Co-immunoprecipitation, competition binding assays, RNAi, kinase activity assays in human cells

   PMID:20624913

   Open questions at the time

   • Structural basis for selective binding of MOB2 to unphosphorylated NDR was not determined
   • In vivo physiological contexts where MOB2-mediated NDR inhibition is critical were unclear
5. 2011 High

   CDK-dependent phosphorylation of fungal Mob2 was shown to be required for hyphal morphogenesis, linking cell-cycle kinase signaling to Mob2-Cbk1 pathway output and polarisome maintenance at hyphal tips.

   Evidence CDK phosphosite mutagenesis, phenotypic and localization analysis in C. albicans

   PMID:21593210

   Open questions at the time

   • Whether CDK phosphorylation alters Mob2-Cbk1 binding affinity or Mob2 localization directly was not biochemically resolved
   • Relevance of analogous phosphorylation events on mammalian MOB2 was unknown
6. 2011 Medium

   Mouse Mob2 was linked to neurite outgrowth and actin cytoskeleton remodeling via phospho-Moesin, providing the first mammalian neuronal function for MOB2.

   Evidence RNAi and overexpression in Neuro2A cells with phospho-Moesin readout

   PMID:21237165

   Open questions at the time

   • Whether MOB2 acts through NDR kinases or an independent pathway in neurite formation was not determined
   • Moesin regulation was correlative; direct mechanism was not established
7. 2013 Medium

   Drosophila genetic analysis demonstrated that Mob2 acts specifically through the NDR kinase Tricornered (not Warts/LATS) to regulate presynaptic NMJ morphology, clarifying NDR-kinase specificity of MOB2 in a neuronal context.

   Evidence Genetic mapping, rescue, and dose-dependent dominant interactions at the Drosophila NMJ

   PMID:23979583

   Open questions at the time

   • Whether MOB2 activates or inhibits Tricornered in this context was not biochemically resolved
   • Downstream substrates of Trc mediating NMJ growth were not identified
8. 2018 Medium

   In vivo cortical knockdown revealed that MOB2 controls neuronal migration and cilia positioning by restraining Filamin A phosphorylation, placing MOB2 downstream of the protocadherin-family protein Dchs1 in a neuronal positioning pathway.

   Evidence In utero electroporation knockdown in mouse cortex, phospho-Filamin A analysis, epistasis with Dchs1

   PMID:29593499

   Open questions at the time

   • Kinase responsible for Filamin A hyperphosphorylation upon MOB2 loss was not identified
   • Whether this pathway involves NDR kinase modulation was not tested
9. 2020 Medium

   MOB2 was established as a tumor-suppressive factor in glioblastoma that physically interacts with PKA and promotes cAMP/PKA-dependent inactivation of the FAK/Akt axis, connecting MOB2 to integrin signaling and cancer cell invasion.

   Evidence Co-IP for PKA, overexpression/knockdown, pharmacological modulation (Forskolin, H89), xenograft models in GBM cells

   PMID:32286266

   Open questions at the time

   • Direct binding interface between MOB2 and PKA subunits was not mapped
   • Relationship between MOB2-PKA and MOB2-NDR functions was not clarified
10. 2025 Medium

    Conditional knockout demonstrated that astrocytic MOB2 activates PI3K-AKT signaling to promote A1-to-A2 reactive astrocyte conversion after spinal cord injury, with pharmacological AKT activation rescuing the phenotype.

    Evidence GFAP-Cre conditional knockout, primary astrocyte models, PI3K-AKT pathway analysis, sc79 rescue in vivo

    PMID:39863205

    Open questions at the time

    • Mechanism by which MOB2 activates PI3K-AKT is unknown — whether through NDR inhibition or an independent route
    • Whether MOB2 loss affects astrocyte-neuron signaling beyond phenotype switching was not explored
11. 2026 Medium

    MOB2 depletion was found to sensitize p53-wild-type lung cancer cells to PARP inhibitors through enhanced p53 phosphorylation and persistent DNA damage, revealing a role for MOB2 in the DNA damage response that depends on functional p53.

    Evidence siRNA knockdown, clonogenic and comet assays, γH2AX immunofluorescence, caspase-3 activity, p53 reconstitution

    PMID:41899447

    Open questions at the time

    • Mechanism linking MOB2 to p53 phosphorylation and DNA repair proficiency is unknown
    • Whether MOB2's NDR-regulatory or PKA-regulatory functions mediate DNA damage sensitivity was not tested

• A unified mechanistic model integrating MOB2's NDR-inhibitory, PKA-stimulatory, and PI3K-AKT-activating functions remains unresolved; whether these represent independent activities or converge through a common scaffolding mechanism is unknown.
• No structural data exist for MOB2 in complex with any partner
• Post-translational regulation of mammalian MOB2 (analogous to CDK phosphorylation in fungi) has not been characterized
• Conditional knockout phenotypes in tissues beyond brain and spinal cord have not been reported