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PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions.

ABSTRACT: Tiam1 is one of the most extensively analyzed activators of the small GTPase Rac. However, fundamental aspects of its regulation are poorly understood. Here we demonstrate that Tiam1 is functionally suppressed by internal interactions and that the PAR complex participates in its full activation. The N-terminal region of Tiam1 binds to the protein-binding and catalytic domains to inhibit its localization and activation. Atypical PKCs phosphorylate Tiam1 to relieve its intramolecular interactions, and the subsequent stabilization of its interaction with PAR3 allows it to exert localized activity. By analyzing Tiam1 regulation by PAR3-aPKC within the context of PDGF signaling, we also show that PAR3 directly binds PDGF receptor ?. Thus we provide the first evidence for the negative regulation of Tiam1 by internal interactions, elucidate the nature of Tiam1 regulation by the PAR complex, and reveal a novel role for the PAR complex in PDGF signaling.

SUBMITTER: Matsuzawa K

PROVIDER: S-EPMC4850038 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions.

Matsuzawa Kenji K Akita Hiroki H Watanabe Takashi T Kakeno Mai M Matsui Toshinori T Wang Shujie S Kaibuchi Kozo K

Molecular biology of the cell 20160303 9

Tiam1 is one of the most extensively analyzed activators of the small GTPase Rac. However, fundamental aspects of its regulation are poorly understood. Here we demonstrate that Tiam1 is functionally suppressed by internal interactions and that the PAR complex participates in its full activation. The N-terminal region of Tiam1 binds to the protein-binding and catalytic domains to inhibit its localization and activation. Atypical PKCs phosphorylate Tiam1 to relieve its intramolecular interactions, ...[more]

PMID: 26941335

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Project description:Prostate cancer (PCa) is one of the most frequent tumors and leading cause of cancer deaths among males worldwide. The majority of deaths are due to recurrence and subsequent development of the metastatic cancer. Although loss or dislocalization of polarity proteins has been implicated in embryogenesis deficiency and tumorigenesis, association of polarity protein expression levels with tumor metastasis remains unclear.Bioinformatics, qRT-PCR, western blot and immunohistochemical (IHC) analyses were used to examine expression of Par3, a key component of polarity-associated partitioning defective (PAR) complex, in primary and metastatic clinical PCa samples. Loss-of-function and gain-of-function studies in vitro and in vivo were performed to determine the functions of Par3 during metastasis of PCa. Co-immunoprecipitation (co-IP), western blot, immunofluorescence (IF), chromatin immunoprecipitation (ChIP) and qRT-PCR analyses were conducted to investigate the underlying mechanism for the function of Par3 on PCa metastasis.In this study, we found that elevated expression of Par3 is positively associated with PCa metastasis. Knockdown of Par3 inhibits PCa cell migration and invasion in vitro and tumor metastasis in vivo, whereas overexpression of Par3 yields the opposite results. Mechanistically, Par3 suppresses phosphorylation of LATS to inactivate the Hippo pathway and enhances nuclear translocation of YAP by sequestrating KIBRA from the KIBRA/Merlin/FRMD6 complex and forming a Par3/aPKC/KIBRA complex. Stable knockdown of Par3 leads to restoration of the KIBRA/Merlin/FRMD6 complex and activation of the Hippo pathway, and then results in an inhibition on YAP nuclear translocation. In addition, in conjunction with the TEA domain (TEAD) transcription factor family, intranuclear YAP promotes the transcription of several pro-metastatic genes such as the matrix metalloproteinase (MMP) family, Zeb1, Snail1 and Twist1. Moreover, knockdown of Par3 downregulates expression of these pro-metastatic genes.Our findings indicate that elevated expression of Par3 promotes PCa metastasis via KIBRA sequestration-mediated inactivation of the Hippo pathway to upregulate expression of pro-metastatic genes. Downregulation of Par3 expression may serve as a potential treatment approach for PCa metastasis by activating the Hippo pathway.

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PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions.

Publications

PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions.

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