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Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins.

ABSTRACT: EGFR and Hippo signaling pathways both control growth and, when dysregulated, contribute to tumorigenesis. We find that EGFR activates the Hippo pathway transcription factor Yorkie and demonstrate that Yorkie is required for the influence of EGFR on cell proliferation in Drosophila. EGFR regulates Yorkie through the influence of its Ras-MAPK branch on the Ajuba LIM protein Jub. Jub is epistatic to EGFR and Ras for Yorkie regulation, Jub is subject to MAPK-dependent phosphorylation, and EGFR-Ras-MAPK signaling enhances Jub binding to the Yorkie kinase Warts and the adaptor protein Salvador. An EGFR-Hippo pathway link is conserved in mammals, as activation of EGFR or RAS activates the Yorkie homolog YAP, and EGFR-RAS-MAPK signaling promotes phosphorylation of the Ajuba family protein WTIP and also enhances WTIP binding to the Warts and Salvador homologs LATS and WW45. Our observations implicate the Hippo pathway in EGFR-mediated tumorigenesis and identify a molecular link between these pathways.

SUBMITTER: Reddy BV

PROVIDER: S-EPMC3624988 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins.

Reddy B V V G BV Irvine Kenneth D KD

Developmental cell 20130301 5

EGFR and Hippo signaling pathways both control growth and, when dysregulated, contribute to tumorigenesis. We find that EGFR activates the Hippo pathway transcription factor Yorkie and demonstrate that Yorkie is required for the influence of EGFR on cell proliferation in Drosophila. EGFR regulates Yorkie through the influence of its Ras-MAPK branch on the Ajuba LIM protein Jub. Jub is epistatic to EGFR and Ras for Yorkie regulation, Jub is subject to MAPK-dependent phosphorylation, and EGFR-Ras- ...[more]

PMID: 23484853

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Project description:Studies in yeast first delineated the function of Mob proteins in kinase pathways that regulate cell division and shape; in multicellular eukaryotes Mobs regulate tissue growth and morphogenesis. In animals, Mobs are adaptors in Hippo signaling, an intracellular signal-transduction pathway that restricts growth, impacting the development and homeostasis of animal organs. Central to Hippo signaling are the Nuclear Dbf2-Related (NDR) kinases, Warts and LATS1 and LATS2, in flies and mammals, respectively. A second Hippo-like signaling pathway has been uncovered in animals, which regulates cell and tissue morphogenesis. Central to this emergent pathway are the NDR kinases, Tricornered, STK38, and STK38L. In Hippo signaling, NDR kinase activation is controlled by three activating interactions with a conserved set of proteins. This review focuses on one co-activator family, the highly conserved, non-catalytic Mps1-binder-related (Mob) proteins. In this context, Mobs are allosteric activators of NDR kinases and adaptors that contribute to assembly of multiprotein NDR kinase activation complexes. In multicellular eukaryotes, the Mob family has expanded relative to model unicellular yeasts; accumulating evidence points to Mob functional diversification. A striking example comes from the most sequence-divergent class of Mobs, which are components of the highly conserved Striatin Interacting Phosphatase and Kinase (STRIPAK) complex, that antagonizes Hippo signaling. Mobs stand out for their potential to modulate the output from Hippo and Hippo-like kinases, through their roles both in activating NDR kinases and in antagonizing upstream Hippo or Hippo-like kinase activity. These opposing Mob functions suggest that they coordinate the relative activities of the Tricornered/STK38/STK38L and Warts/LATS kinases, and thus have potential to assemble nodes for pathway signaling output. We survey the different facets of Mob-dependent regulation of Hippo and Hippo-like signaling and highlight open questions that hinge on unresolved aspects of Mob functions.

Dataset Information

Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins.

Publications

Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins.

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