NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidylserine to Sec15

Chiba, Shuhei; Amagai, Yuta; Homma, Yuta; Fukuda, Mitsunori; Mizuno, Kensaku

doi:10.1038/emboj.2013.32

Cited by 83 publications

(103 citation statements)

References 47 publications

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“…Rabin8, the homolog of Sec2p, is recruited to the pericentrosome at the base of the cilia by binding to Rab11 (10), the homolog of Ypt32p, but it also binds to the mammalian homolog of Sec15p. Interestingly, phosphorylation of Rabin8 at S272, a site that aligns with the 181-188 region of Sec2p, promotes binding to Sec15p and inhibits binding to Rab11 (16), exactly paralleling the regulation we report here. Although Rabin8 does not bind to PI(4)P, as does Sec2p, it does bind to phosphatidylserine, and this affinity is reduced by phosphorylation, just as the affinity of Sec2p for PI(4)P is reduced by phosphorylation (16).…”

Section: Discussionsupporting

confidence: 54%

“…Phosphorylation of Rabin8 at serine 272 is directed by the NDR2 kinase (16,17). The yeast NDR kinase, Cbk1, binds to Sec2p and will phosphorylate Sec2p in vitro (20).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, serines 181, 186, and 188 lie within a large serine/threonine patch of seven residues, and alignment of Sec2p with its mammalian homolog, Rabin8, shows that this patch is close to the STSS 243 stretch that very recently has been shown to be subject to phosphorylation in Rabin8 (Fig. 2B) (16,17). This general region of Sec2p is involved in binding to both Ypt32p-GTP and Sec15p.…”

Section: Phosphorylation Of Sec2p Increases Binding To the Exocyst Comentioning

confidence: 99%

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Phosphorylation of the Rab exchange factor Sec2p directs a switch in regulatory binding partners

Stalder¹,

Mizuno-Yamasaki²,

Ghassemian

et al. 2013

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

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Sec2p is a guanine nucleotide exchange factor that promotes exocytosis by activating the Rab GTPase Sec4p. Sec2p is highly phosphorylated, and we have explored the role of phosphorylation in the regulation of its function. We have identified three phosphosites and demonstrate that phosphorylation regulates the interaction of Sec2p with its binding partners Ypt32p, Sec15p, and phosphatidyl-inositol-4-phosphate. In its nonphosphorylated form, Sec2p binds preferentially to the upstream Rab, Ypt32p-GTP, thus forming a Rab guanine nucleotide exchange factor cascade that leads to the activation of the downstream Rab, Sec4p. The nonphosphorylated form of Sec2p also binds to the Golgi-associated phosphatidyl-inositol-4-phosphate, which works in concert with Ypt32p-GTP to recruit Sec2p to Golgi-derived secretory vesicles. In contrast, the phosphorylated form of Sec2p binds preferentially to Sec15p, a downstream effector of Sec4p and a component of the exocyst tethering complex, thus forming a positivefeedback loop that prepares the secretory vesicle for fusion with the plasma membrane. Our results suggest that the phosphorylation state of Sec2p can direct a switch in its regulatory binding partners that facilitates maturation of the secretory vesicle and helps to promote the directionality of vesicular transport.

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Section: Discussionsupporting

confidence: 54%

“…Phosphorylation of Rabin8 at serine 272 is directed by the NDR2 kinase (16,17). The yeast NDR kinase, Cbk1, binds to Sec2p and will phosphorylate Sec2p in vitro (20).…”

Section: Discussionmentioning

confidence: 99%

Section: Phosphorylation Of Sec2p Increases Binding To the Exocyst Comentioning

confidence: 99%

See 1 more Smart Citation

Phosphorylation of the Rab exchange factor Sec2p directs a switch in regulatory binding partners

Stalder¹,

Mizuno-Yamasaki²,

Ghassemian

et al. 2013

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

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“…NDR2 phosphorylation was implicated in primary ciliogenesis in mammalian cells (36). In flies, this phosphorylation event was shown to be important for dendrite arborization (37).…”

Section: Discussionmentioning

confidence: 99%

“…Although our study focuses on the effect of ERK1/2 on the activation of Rabin8, previous studies have shown the phosphorylation of Rabin8 by NDR2 at a different site, S272 (36). NDR2 phosphorylation was implicated in primary ciliogenesis in mammalian cells (36).…”

Section: Discussionmentioning

confidence: 99%

Activation of Rab8 guanine nucleotide exchange factor Rabin8 by ERK1/2 in response to EGF signaling

Wang

Ren

et al. 2014

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

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Exocytosis is tightly regulated in many cellular processes, from neurite expansion to tumor proliferation. Rab8, a member of the Rab family of small GTPases, plays an important role in membrane trafficking from the trans-Golgi network and recycling endosomes to the plasma membrane. Rabin8 is a guanine nucleotide exchange factor (GEF) and major activator of Rab8. Investigating how Rabin8 is activated in cells is thus pivotal to the understanding of the regulation of exocytosis. Here we show that phosphorylation serves as an important mechanism for Rabin8 activation. We identified Rabin8 as a direct phospho-substrate of ERK1/2 in response to EGF signaling. At the molecular level, ERK phosphorylation relieves the autoinhibition of Rabin8, thus promoting its GEF activity. We further demonstrate that blocking ERK1/2-mediated phosphorylation of Rabin8 inhibits transferrin recycling to the plasma membrane. Together, our results suggest that ERK1/2 activate Rabin8 to regulate vesicular trafficking to the plasma membrane in response to extracellular signaling.Rab GTPases | Rab8 | guanine nucleotide exchange factor | ERK | phosphorylation

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Mosaic deletion of EXOC6B: Further evidence for an important role of the exocyst complex in the pathogenesis of intellectual disability

Evers

Maas

Koch

et al. 2014

American J of Med Genetics Pt A

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We describe a boy with developmental delay, speech delay, and minor dysmorphic features with a heterozygous de novo ∼460 kb deletion at 2p13.2 involving only parts of EXOC6B present in about 50% of lymphocytes. This widely expressed gene encodes the exocyst component 6B, which is part of a multiprotein complex required for targeted exocytosis. Little is known about the effect of EXOC6B haploinsufficiency. In 2008, a patient with a complex syndromic phenotype, including left renal agenesis, neutropenia, recurrent pulmonary infections, long bone diaphysis broadening, growth retardation, and developmental delay (DD) was found to carry a de novo translocation t(2;7) involving TSN3 and EXOC6B. Further characterization of the translocation indicated that disruption of TSN3 may be responsible for the skeletal phenotype. Recently, a heterozygous deletion of EXOC6B along with a deletion of the CYP26B1 gene has been reported in a boy with intellectual disability, speech delay, hyperactivity, facial asymmetry, a dysplastic ear, brachycephaly, and mild joint contractures. Additionally, disruption of EXOC6B by a de novo balanced translocation t(2;8) has been described in a patient with developmental delay, epilepsy, autistic and aggressive behavior. This is the first report of a de novo deletion affecting only EXOC6B in an individual with developmental delay. In conclusion, based on our findings and recent data from the literature, there is evidence that EXOC6B and the exocyst complex might play an important role in the molecular pathogenesis of intellectual disability.

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NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidylserine to Sec15

Cited by 83 publications

References 47 publications

Phosphorylation of the Rab exchange factor Sec2p directs a switch in regulatory binding partners

Phosphorylation of the Rab exchange factor Sec2p directs a switch in regulatory binding partners

Activation of Rab8 guanine nucleotide exchange factor Rabin8 by ERK1/2 in response to EGF signaling

Mosaic deletion of EXOC6B: Further evidence for an important role of the exocyst complex in the pathogenesis of intellectual disability

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