Arf guanine nucleotide-exchange factors BIG1 and BIG2 regulate nonmuscle myosin IIA activity by anchoring myosin phosphatase complex

Kang, Le; Li, Chun Chun; Guan, Yong Liang; Moss, Joel; Vaughan, Martha

doi:10.1073/pnas.1312531110

Cited by 31 publications

(27 citation statements)

References 63 publications

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“…Failure of overexpression of BIG1-C and BIG1-S (BIG1-Sec7, 698-887) fragments to reverse the effects of BIG1 depletion, although both BIG1-N and -F were effective (Fig. S5B), excluded a role for the BIG1 C terminus in S675 phosphorylation (43). We confirmed (Fig.…”

Section: Resultssupporting

confidence: 64%

Enhancement of β-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals

Kang

Katō

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Multifunctional β-catenin, with critical roles in both cell-cell adhesion and Wnt-signaling pathways, was among HeLa cell proteins coimmunoprecipitated by antibodies against brefeldin A-inhibited guanine nucleotide-exchange factors 1 and 2 (BIG1 or BIG2) that activate ADP-ribosylation factors (Arfs) by accelerating the replacement of bound GDP with GTP. BIG proteins also contain A-kinase anchoring protein (AKAP) sequences that can act as scaffolds for multimolecular assemblies that facilitate and limit cAMP signaling temporally and spatially. Direct interaction of BIG1 N-terminal sequence with β-catenin was confirmed using yeast two-hybrid assays and in vitro synthesized proteins. Depletion of BIG1 and/or BIG2 or overexpression of guanine nucleotide-exchange factor inactive mutant, but not wild-type, proteins interfered with β-catenin trafficking, leading to accumulation at perinuclear Golgi structures. Both phospholipase D activity and vesicular trafficking were required for effects of BIG1 and BIG2 on β-catenin activation. Levels of PKAphosphorylated β-catenin S675 and β-catenin association with PKA, BIG1, and BIG2 were also diminished after BIG1/BIG2 depletion. Inferring a requirement for BIG1 and/or BIG2 AKAP sequence in PKA modification of β-catenin and its effect on transcription activation, we confirmed dependence of S675 phosphorylation and transcription coactivator function on BIG2 AKAP-C sequence.ADP-ribosylation factor | cell migration | AKAP | phospholipase D M ultifunctional β-catenin is an essential component of intercellular adherens junctions (AJs) that link cell surface cadherin and actin cytoskeleton via interactions with both. β-catenin is also a transcriptional coactivator in several pathways, including Wnt-initiated signaling (1, 2), which is critical in embryonic development and tissue homeostasis or pathology (2, 3). In the absence of "canonical" catenin-dependent Wnt signaling, cytoplasmic β-catenin is maintained at low levels via phosphorylations of S45 and S33, S37 and T41 by, respectively, casein kinase-1 and glycogen synthase kinase-3 (GSK-3) (1, 2). Subsequent degradation of β-catenin via an ubiquitin/proteasome pathway involves axin and adenomatous polyposis coli (APC) as scaffold proteins, plus β-transducin repeat-containing protein (β-TrCP), an E3 ubiquitin ligase. In one well-known model, binding of Wnt to Frizzled (Fz) and its coreceptor low-density lipoprotein receptor-like protein 5 or 6 (LRP5/6) resulted in GSK-3 sequestration in multivesicular bodies, thereby reducing its cytosolic level (4, 5). With lower GSK-3 activity, "stabilized" β-catenin (1, 2) entered the nucleus and, along with members of the T-cell factor (TCF)/lymphoid enhancer factor (LEF) family, activated transcription via Wnt-target gene promoters, including c-myc and cyclin D1 (6-8). In β-catenin knockout mice, embryogenesis was arrested at gastrulation (9) and aberrant Wnt signaling led to tumor development (2, 3).Although relationships between labile and stabilized β-catenin pools remain poorly understood, ...

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Section: Resultssupporting

confidence: 64%

Enhancement of β-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals

Kang

Katō

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…HeLa cells were incubated with 10 lM oridonin 36 h before plating in the upper chamber, and they were allowed to migrate for 6 h. As shown in Fig. 4a, b, HeLa cells incubated with oridonin showed significantly reduced motility compared with control cells or DMSO-treated cells, consistent with the previous report (Le et al 2013). …”

Section: Effects Of Oridonin On Cell Migrationsupporting

confidence: 89%

“…Transwell migration assays were performed as previously described (Le et al 2013). Briefly, the lower surface of transwell membranes (6.5 mm diameter, 8 lm pore; Corning Life Sciences, Shanghai, China) were coated (overnight, 4°C) with 10 lg/mL fibronectin (Millipore).…”

Section: Migration Assaysmentioning

confidence: 99%

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Oridonin suppress cell migration via regulation of nonmuscle myosin IIA

Sun

Zhao

et al. 2014

Cytotechnology

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Oridonin, which is isolated from Chinese herb Rabdosia rubescens (Hemsl.) Hara, has been implicated in regulation of tumor cell migration and invasion. In this study, treatment with oridonin enhanced the phosphorylation of myosin regulatory light chain (T18/S19) that regulates the ATPase activity of myosin IIA. Meanwhile, stress fibers were significantly more prominent after oridonin incubation, which impaired cell migration in transwell migration assays. All of these effects may be caused by the decreased interaction between myosin IIA and myosin phosphatase complex, but not kinases. Our data provide clear evidence of this novel pharmacological function for oridonin in treating cancer cell migration.

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“…Two Arf GEFs, BIG1 and BIG2, negatively regulate NM2 activity. 37 The BIGs promote dephosphorylation of RLC by stabilizing the phosphatase (PP1/PP1cd)-NM2A interaction and mediating a decrease in NM2-dependent contractility. Arfs may also regulate NM2 by mechanism involving Rho family members.…”

Section: Asap1 and Nonmuscle Myosin 2a (Nm2a)mentioning

confidence: 99%

Arf GAPs and molecular motors

et al. 2017

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Arf GTPase-activating proteins (Arf GAPs) were first identified as regulators of the small GTP-binding proteins ADP-ribosylation factors (Arfs). The Arf GAPs are a large family of proteins in metazoans, outnumbering the Arfs that they regulate. The members of the Arf GAP family have complex domain structures and some have been implicated in particular cellular functions, such as cell migration, or with particular pathologies, such as tumor invasion and metastasis. The specific effects of Arfs sometimes depend on the Arf GAP involved in their regulation. These observations have led to speculation that the Arf GAPs themselves may affect cellular activities in capacities beyond the regulation of Arfs. Recently, 2 Arf GAPs, ASAP1 and AGAP1, have been found to bind directly to and influence the activity of myosins and kinesins, motor proteins associated with filamentous actin and microtubules, respectively. The Arf GAP-motor protein interaction is critical for cellular behaviors involving the actin cytoskeleton and microtubules, such as cell migration and other cell movements. Arfs, then, may function with molecular motors through Arf GAPs to regulate microtubule and actin remodeling.

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Arf guanine nucleotide-exchange factors BIG1 and BIG2 regulate nonmuscle myosin IIA activity by anchoring myosin phosphatase complex

Cited by 31 publications

References 63 publications

Enhancement of β-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals

Enhancement of β-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals

Oridonin suppress cell migration via regulation of nonmuscle myosin IIA

Arf GAPs and molecular motors

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