Pleckstrin homology (PH) like domains – versatile modules in protein–protein interaction platforms

Scheffzek, Klaus; Welti, Stefan

doi:10.1016/j.febslet.2012.06.006

Cited by 126 publications

(115 citation statements)

References 125 publications

(159 reference statements)

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“…Thus, PH-like domains are more versatile than initially thought. Our finding of a phosphoinositideindependent interaction between the SLAT PH domain and active Rap1 supports the emerging, although underappreciated, role of PH domains in protein-protein interactions (Balla, 2005;Kavran et al, 1998;Lemmon, 2004;Scheffzek and Welti, 2012), including our recent finding that SLAT regulates Ca 2+ signaling through a direct interaction of its PH domain with the IP 3 R1 (also known as ITPR1) (Fos et al, 2014). Other examples include the interactions of PKD1 with active Rap1 (Medeiros et al, 2005), RIAM with SKAP-55 (Menasche et al, 2007b) and Itk kinase with calmodulin (Wang et al, 2014) through their respective PH domains.…”

Section: Discussionsupporting

confidence: 80%

SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1

Côte

Fos

Canonigo-Balancio

et al. 2015

Journal of Cell Science

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SLAT (also known as DEF6) promotes T cell activation and differentiation by regulating NFAT-Ca 2+ signaling. However, its role in TCR-mediated inside-out signaling, which induces integrin activation and T cell adhesion, a central process in T cell immunity and inflammation, has not been explored. Here, we show that SLAT is crucial for TCR-induced adhesion to ICAM-1 and affinity maturation of LFA-1 in CD4 + T cells. Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4 + T cell adhesion. Finally, we established that a constitutively active form of Rap1, which is present at the plasma membrane, rescues the defective LFA-1 activation and ICAM-1 adhesion in SLAT-deficient (Def6 −/− ) T cells. These findings ascribe a new function to SLAT, and identify Rap1 as a target of SLAT function in TCR-mediated inside-out signaling.

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Section: Discussionsupporting

confidence: 80%

SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1

Côte

Fos

Canonigo-Balancio

et al. 2015

Journal of Cell Science

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“…Nonetheless, the higher affinity of PH domain for the receptor compared with CTD and the ability of the 5-HT 6 inverse agonist to prevent association of 5-HT 6 receptor with PH domain but not with CTD suggest a prominent role of PH domain in the interaction between both protein partners. PH-like domains have long been associated with proteins involved in signal transduction (25). Neurofibromin PH domain is adjacent to the central GTPase-activating proteinrelated domain and the Sec14-homologous Sec domain that interacts with glycerophospholipids (26).…”

Section: Discussionmentioning

confidence: 99%

Physical interaction between neurofibromin and serotonin 5-HT ₆ receptor promotes receptor constitutive activity

Nadim

Chaumont‐Dubel

Madouri

et al. 2016

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

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Active G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT 6 ) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the RasGTPase activating protein (Ras-GAP) neurofibromin, a 5-HT 6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT 6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT 6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT 6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1 +/− mice compared with WT mice. Moreover, systemic administration of a 5-HT 6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1 +/− mice. Collectively, these findings suggest that disrupting 5-HT 6 receptor-neurofibromin interaction prevents agonist-independent 5-HT 6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients.5-HT 6 receptor | constitutive activity | G protein-coupled receptor | neurofibromin | neurofibromatosis type 1

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“…4,5 The alternate site is on the opposite side of the b1/b2 loop, and includes interaction with the b5/b6 loop, corresponding to the phosphoinositide binding site in the PH domains of spectrin, TIAM1 and Slm1, for example. 4,5,102,103 The crystal structures of the unliganded ASAP1 PH domain and the PH domain with diC4-PtdIns(4,5)P 2 (a water soluble form of PI (4,5)P 2 with 4 carbon acyl groups) were determined (Fig. 6).…”

mentioning

confidence: 99%

Allosteric properties of PH domains in Arf regulatory proteins

et al. 2016

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Pleckstrin Homology (PH) domains bind phospholipids and proteins. They are critical regulatory elements of a number enzymes including guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) for Ras-superfamily guanine nucleotide binding proteins such as ADP-ribosylation factors (Arfs). Recent studies have indicated that many PH domains may bind more than one ligand cooperatively. Here we discuss the molecular basis of PH domain-dependent allosteric behavior of 2 ADPribosylation factor exchange factors, Grp1 and Brag2, cooperative binding of ligands to the PH domains of Grp1 and the Arf GTPase-activating protein, ASAP1, and the consequences for activity of the associated catalytic domains.

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Pleckstrin homology (PH) like domains – versatile modules in protein–protein interaction platforms

Cited by 126 publications

References 125 publications

SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1

SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1

Physical interaction between neurofibromin and serotonin 5-HT ₆ receptor promotes receptor constitutive activity

Allosteric properties of PH domains in Arf regulatory proteins

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Pleckstrin homology (PH) like domains – versatile modules in protein–protein interaction platforms

Cited by 126 publications

References 125 publications

SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1

SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1

Physical interaction between neurofibromin and serotonin 5-HT 6 receptor promotes receptor constitutive activity

Allosteric properties of PH domains in Arf regulatory proteins

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Physical interaction between neurofibromin and serotonin 5-HT ₆ receptor promotes receptor constitutive activity