Signaling by Phosphoinositide-3,4,5-Trisphosphate Through Proteins Containing Pleckstrin and Sec7 Homology Domains

Klarlund, Jes K.; Guilherme, Adı́lson; Holik, John; Virbasius, Joseph V.; Chawla, Anil; Czech, Michael P.

doi:10.1126/science.275.5308.1927

Cited by 405 publications

(379 citation statements)

References 24 publications

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“…The microarray data show that DSP-10/MKP-5 levels are reduced in PTEN-null tumors, suggesting that JNK activity may be increased in PTEN- null cancers. A third gene in the classifier, Regulator of G protein signaling 1, is noteworthy because it specifically binds to and is inhibited by the PTEN substrate phosphatidylinositol triphosphate (PIP3) (39,40), raising the possibility of feedback control of PI3K signaling.…”

Section: Discussionmentioning

confidence: 99%

Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer

Mehrian‐Shai

Chen

Shi

et al. 2007

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

169

125

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Section: Discussionmentioning

confidence: 99%

Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer

Mehrian‐Shai

Chen

Shi

et al. 2007

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

169

125

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“…In addition, Arf proteins are affected by phosphoinositides. Both Arf exchange factors (10,(53)(54)(55)(56) and GAPs (27,28,42) contain PH domains and are activated by phosphoinositides. Thus, PtdInsP 2 could function as a Effect of ASAP1 overexpression on cell spreading rate.…”

Section: Discussionmentioning

confidence: 99%

The Arf GTPase-activating protein ASAP1 regulates the actin cytoskeleton

Randazzo

Andrade

Miura

et al. 2000

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

199

181

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Arf family GTP-binding proteins are best characterized as regulators of membrane traffic, but recent studies indicate an additional role in cytoskeletal organization. An Arf GTPase-activating protein of the centaurin ␤ family, ASAP1 (also known as centaurin ␤4), binds Arf and two other known regulators of the actin cytoskeleton, the tyrosine kinase Src and phosphatidylinositol 4,5-bisphosphate. In this paper, we show that ASAP1 localizes to focal adhesions and cycles with focal adhesion proteins when cells are stimulated to move. Overexpression of ASAP1 altered the morphology of focal adhesions and blocked both cell spreading and formation of dorsal ruffles induced by platelet-derived growth factor (PDGF). On the other hand, ASAP1, with a mutation that disrupted GTPase-activating protein activity, had a reduced effect on cell spreading and increased the number of cells forming dorsal ruffles in response to PDGF. These data support a role for an Arf GTPase-activating protein, ASAP1, as a regulator of cytoskeletal remodeling and raise the possibility that the Arf pathway is a target for PDGF signaling.

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“…Cytohesins also interact with PI(3,4,5)P 3 , with splice variants with a di-glycine instead of a tri-glycine in the b1-b2 loop of the PH domain showing a marked preference for this rare phosphoinositide. [50][51][52] The polybasic region in the C-terminus of the PH domain of cytohesins makes additional contributions to their interaction with acidic membranes. 53 Biophysical and molecular dynamics simulations suggest that the PH domain and the polybasic region bind additional acidic lipids at non-canonical binding sites.…”

Section: Regulation Of Ph Domain-containing Arfgefs By Membranesmentioning

confidence: 99%

Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

2016

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Arf GTPases assemble protein complexes on membranes to carry out major functions in cellular traffic. An essential step is their activation by guanine nucleotide exchange factors (GEFs), whose Sec7 domain stimulates GDP/GTP exchange. ArfGEFs form 2 major families: ArfGEFs with DCB, HUS and HDS domains (GBF1 and BIG1/BIG2 in humans), which act at the Golgi; and ArfGEFs with a Cterminal PH domain (cytohesin, EFA6 and BRAG), which function at the plasma membrane and endosomes. In addition, pathogenic bacteria encode an ArfGEF with a unique membrane-binding domain. Here we review the allosteric regulation of Arf GTPases and their GEFs at the membrane interface. Membranes contribute several regulatory layers: at the GTPase level, where activation by GTP is coupled to membrane recruitment by a built-in structural device; at the Sec7 domain, which manipulates this device to ensure that Arf-GTP is attached to membranes; and at the level of noncatalytic ArfGEF domains, which form direct or GTPase-mediated interactions with membranes that enable a spectacular diversity of regulatory regimes. Notably, we show here that membranes increase the efficiency of a large ArfGEF (human BIG1) by 32-fold by interacting directly with its Nterminal DCB and HUS domains. The diversity of allosteric regulatory regimes suggests that ArfGEFs can function in cascades and circuits to modulate the shape, amplitude and duration of Arf signals in cells. Because Arf-like GTPases feature autoinhibitory elements similar to those of Arf GTPases, we propose that their activation also requires allosteric interactions of these elements with membranes or other proteins.

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Signaling by Phosphoinositide-3,4,5-Trisphosphate Through Proteins Containing Pleckstrin and Sec7 Homology Domains

Cited by 405 publications

References 24 publications

Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer

Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer

The Arf GTPase-activating protein ASAP1 regulates the actin cytoskeleton

Allosteric regulation of Arf GTPases and their GEFs at the membrane interface

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