Non-canonical Interaction of Phosphoinositides with Pleckstrin Homology Domains of Tiam1 and ArhGAP9

Ceccarelli, Derek F.; Blasutig, Ivan M.; Goudreault, Marilyn; Li, Zhiqin; Ruston, Julie; Pawson, Tony; Sicheri, Frank

doi:10.1074/jbc.m700505200

Cited by 91 publications

(109 citation statements)

References 47 publications

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“…Other basic residues located within the domain vary from domain to domain and can provide a stronger binding affinity and create a unique binding pocket. Two distinct members of the PH domain family (TIAM1 and ARHGAP9) (39) were recently discovered that bind membranes through a site on the opposite side of the b1-b2 loop, suggesting that there are still novel PH domains to be discovered within the genome.…”

Section: Ph Domainsmentioning

confidence: 99%

Lipid binding domains: more than simple lipid effectors

Stahelin

2009

Journal of Lipid Research

124

105

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The spatial and temporal regulation of lipid molecules in cell membranes is a hallmark of cellular signaling and membrane trafficking events. Lipid-mediated targeting provides for strict control and versatility, because cell membranes harbor a large number of lipid molecules with variation in head group and acyl chain structures. Signaling and trafficking proteins contain a large number of modular domains that exhibit specific lipid binding properties and play a critical role in their localization and function. Nearly 20 years of research including structural, computational, biochemical and biophysical studies have demonstrated how these lipid-binding domains recognize their target lipid and achieve subcellular localization. The integration of this individual lipid-binding domain data in the context of the fulllength proteins, macromolecular signaling complexes, and the lipidome is only beginning to be unraveled and represents a target of therapeutic development. This review brings together recent findings and classical concepts to concisely summarize the lipid-binding domain field while illustrating where the field is headed and how the gaps may be filled in with new technologies.-Stahelin, R. V. Lipid binding domains: more than simple lipid effectors. J. Lipid Res. 2009. 50: S299-S304.

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Section: Ph Domainsmentioning

confidence: 99%

Lipid binding domains: more than simple lipid effectors

Stahelin

2009

Journal of Lipid Research

124

105

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“…The samples were analyzed by SDS-polyacrylamide gel electrophoresis (PAGE) and Coomassie blue staining. For fluorescence polarization, the purified FERM domain (9) was incubated with BODIPY (dipyrromethene boron difluoride)-labeled phosphoinosotides with C 6 -acyl chains (8). Increasing concentrations of purified protein was added to 12.5 nM fluorescent phosphoinositide in buffer containing 20 mM HEPES [pH 7.0], 150 mM NaCl, and 5 mM ␤-mercaptoethanol.…”

Section: Methodsmentioning

confidence: 99%

Spatial and Temporal Regulation of Focal Adhesion Kinase Activity in Living Cells

Cai¹,

Lietha

Ceccarelli

et al. 2008

Molecular and Cellular Biology

161

158

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Focal adhesion kinase (FAK) is an essential kinase that regulates developmental processes and functions in the pathology of human disease. An intramolecular autoinhibitory interaction between the FERM and catalytic domains is a major mechanism of regulation. Based upon structural studies, a fluorescence resonance energy transfer (FRET)-based FAK biosensor that discriminates between autoinhibited and active conformations of the kinase was developed. This biosensor was used to probe FAK conformational change in live cells and the mechanism of regulation. The biosensor demonstrates directly that FAK undergoes conformational change in vivo in response to activating stimuli. A conserved FERM domain basic patch is required for this conformational change and for interaction with a novel ligand for FAK, acidic phospholipids. Binding to phosphatidylinositol 4,5-bisphosphate (PIP2)-containing phospholipid vesicles activated and induced conformational change in FAK in vitro, and alteration of PIP2 levels in vivo changed the level of activation of the conformational biosensor. These findings provide direct evidence of conformational regulation of FAK in living cells and novel insight into the mechanism regulating FAK conformation.Focal adhesion kinase (FAK) is an essential non-receptor tyrosine kinase, since FAK-null mice exhibit embryonic lethality (21). In endothelial cells, FAK is required for the proper development of the vasculature (5, 51), and in neurons FAK regulates netrin-mediated axon outgrowth and dendrite formation (41,45). In addition to these roles in development, FAK is also implicated in the pathology of disease. FAK expression is required in cardiomyocytes to promote hypertrophy and fibrosis in response to cardiac stress and potentially plays a role in the development of heart disease (18, 42). Overexpression of FAK is observed in many types of cancer (22), and experiments using animal models have implicated FAK in tumor formation and metastasis in a number of neoplasms, including cancer of the brain, breast, and skin (38,39,58).Despite the importance of FAK in controlling multiple developmental and pathological events, the molecular mechanism of regulation remains incompletely elucidated. Like many kinases posttranslation modification, particularly phosphorylation, is a major regulatory mechanism. Tyrosine 397 is the major site of autophosphorylation, and mutation of this site abrogates the biological activity of FAK (47). This site primarily serves a scaffolding function, providing a docking site for a number of proteins containing SH2 domains, including Src and phosphatidylinositol 3-kinase (47). The interaction with FAK occupies both the SH2 and SH3 domains of Src preventing intramolecular inhibitory interactions resulting in stabilization of Src in its active conformation (54). Complex formation also serves to direct Src to its substrates, which include FAK itself. Activated Src phosphorylates FAK on multiple sites, including two tyrosine residues in the activation loop, Y576 and Y577, which function ...

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“…TKS5 is also important for the generation of reactive oxygen species (ROS) Gianni et al, 2009), which might potentiate tyrosine kinase activity at invadopodia and podosomes by inhibiting tyrosine phosphatases Weaver, 2009). Additional potential effectors include Akt (Klippel et al, 1997;Yamaguchi et al, 2011), TIAM1 (Ceccarelli et al, 2007) and other PtdIns(3,4)P 2 -binding partners with unknown functions at invadopodia. Overall, these data suggest that growth-factor-mediated activation of PI3K might affect the formation of invadopodia and podosomes through downstream effectors that regulate Src kinase signaling and actin organization (Fig.…”

Section: Regulation By Phosphatidylinositolsmentioning

confidence: 99%

Signaling inputs to invadopodia and podosomes

Hoshino

Branch

Weaver

2013

Journal of Cell Science

153

175

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SummaryRemodeling of extracellular matrix (ECM) is a fundamental cell property that allows cells to alter their microenvironment and move through tissues. Invadopodia and podosomes are subcellular actin-rich structures that are specialized for matrix degradation and are formed by cancer and normal cells, respectively. Although initial studies focused on defining the core machinery of these two structures, recent studies have identified inputs from both growth factor and adhesion signaling as crucial for invasive activity. This Commentary will outline the current knowledge on the upstream signaling inputs to invadopodia and podosomes and their role in governing distinct stages of these invasive structures. We discuss invadopodia and podosomes as adhesion structures and highlight new data showing that invadopodia-associated adhesion rings promote the maturation of already-formed invadopodia. We present a model in which growth factor stimulation leads to phosphoinositide 3-kinase (PI3K) activity and formation of invadopodia, whereas adhesion signaling promotes exocytosis of proteinases at invadopodia.

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Non-canonical Interaction of Phosphoinositides with Pleckstrin Homology Domains of Tiam1 and ArhGAP9

Cited by 91 publications

References 47 publications

Lipid binding domains: more than simple lipid effectors

Lipid binding domains: more than simple lipid effectors

Spatial and Temporal Regulation of Focal Adhesion Kinase Activity in Living Cells

Signaling inputs to invadopodia and podosomes

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