The PI3K effector Arap3 interacts with the PI(3,4,5)P3 phosphatase SHIP2 in a SAM domain-dependent manner

Raaijmakers, J.H.; Deneubourg, Laurence; Rehmann, Holger; Koning, John de; Zhang, Zhong-Chun; Krugmann, Sonja; Erneux, Christophé; Bos, Johannes L.

doi:10.1016/j.cellsig.2006.12.015

Cited by 61 publications

(52 citation statements)

References 36 publications

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“…ARAP3 is a multimodular protein that can bind to several molecules such as PI(3,4,5)P3 and Src homology 2 domain containing inositol 5-phosphatase 2 (SHIP2) in vitro, possibly through its sterile alpha motif domain (Krugmann et al, 2002;Raaijmakers et al, 2007). Our data revealed the essential role of the phosphotyrosinecontaining region of ARAP3 for the first time.…”

Section: Discussionmentioning

confidence: 72%

ARAP3 inhibits peritoneal dissemination of scirrhous gastric carcinoma cells by regulating cell adhesion and invasion

Yagi¹,

Tanaka

Sasaki

et al. 2010

Oncogene

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During the analysis of phosphotyrosine-containing proteins in scirrhous gastric carcinoma cell lines, we observed an unusual expression of Arf-GAP with Rho-GAP domain, ankyrin repeat and PH domain 3 (ARAP3), a multimodular signaling protein that is a substrate of Src family kinases. Unlike other phosphotyrosine proteins, such as CUB domain-containing protein 1 (CDCP1) and Homo sapiens chromosome 9 open reading frame 10/ oxidative stress-associated Src activator (C9orf10/Ossa), which are overexpressed and hyperphosphorylated in scirrhous gastric carcinoma cell lines, ARAP3 was underexpressed in cancerous human gastric tissues. In this study, we found that overexpression of ARAP3 in the scirrhous gastric carcinoma cell lines significantly reduced peritoneal dissemination. In vitro studies also showed that ARAP3 regulated cell attachment to the extracellular matrix, as well as invasive activities. These effects were suppressed by mutations in the Rho-GTPase-activating protein (GAP) domain or in the C-terminal two tyrosine residues that are phosphorylated by Src. Thus, the expression and phosphorylation state of ARAP3 may affect the invasiveness of cancer by modulating cell adhesion and motility. Our results suggest that ARAP3 is a unique Src substrate that suppresses peritoneal dissemination of scirrhous gastric carcinoma cells.

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Section: Discussionmentioning

confidence: 72%

ARAP3 inhibits peritoneal dissemination of scirrhous gastric carcinoma cells by regulating cell adhesion and invasion

Yagi¹,

Tanaka

Sasaki

et al. 2010

Oncogene

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“…3 Cin85 and Ship-2 are experimentally confirmed binding partners (69,70). Rap1 has been reported to bind to ARAP3 through the RA domain (71).…”

Section: Discussionmentioning

confidence: 99%

ARAP2 Signals through Arf6 and Rac1 to Control Focal Adhesion Morphology*

Chen

Jian

Yoon

et al. 2013

Journal of Biological Chemistry

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Background: ARAP2 is an ArfGAP that regulates focal adhesions (FAs) by an unknown mechanism. Results: ARAP2 activity controlled FA size and regulated cellular Arf6⅐GTP and Rac1⅐GTP. The effect of loss of ARAP2 on FAs was reversed by dominant negative Arf6 or Rac1. Conclusion: ARAP2 functions in part by inhibiting the Arf6/Rac1 pathway. Significance: We describe a mechanism by which an ArfGAP can regulate FAs.

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“…Indeed, a recent study has identified the SAM domain complex of Arap3/ SHIP2 that forms discrete dimers in solution (20). Whether the Arap3/SHIP2 mode of dimerization also involves ML/EH surfaces is unknown.…”

Section: Cnk/hyp Dimerization Is Essential For Raf Signaling In Vivomentioning

confidence: 99%

CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling

Rajakulendran

Sahmi

Kurinov

et al. 2008

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

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RAF kinase functions in the mitogen-activated protein kinase (MAPK) pathway to transmit growth signals to the downstream kinases MEK and ERK. Activation of RAF catalytic activity is facilitated by a regulatory complex comprising the proteins CNK (Connector enhancer of KSR), HYP (Hyphen), and KSR (Kinase Suppressor of Ras). The sterile ␣-motif (SAM) domain found in both CNK and HYP plays an essential role in complex formation. Here, we have determined the x-ray crystal structure of the SAM domain of CNK in complex with the SAM domain of HYP. The structure reveals a single-junction SAM domain dimer of 1:1 stoichiometry in which the binding mode is a variation of polymeric SAM domain interactions. Through in vitro and in vivo mutational analyses, we show that the specific mode of dimerization revealed by the crystal structure is essential for RAF signaling and facilitates the recruitment of KSR to form the CNK/HYP/KSR regulatory complex. We present two docking-site models to account for how SAM domain dimerization might influence the formation of a higher-order CNK/HYP/KSR complex. RAF kinases are downstream effectors of the RAS family of small GTPases (reviewed in ref. 4). Although the events leading to RAS activation are now well understood, the precise mechanism by which activated RAS in turn activates RAF to transduce signals to MEK and ERK remains unclear (5). Studies in Drosophila S2 cells revealed that activation of RAF kinase at sites of RAS-mediated signaling is facilitated by a regulatory complex comprising the proteins CNK (Connector enhancer of KSR), HYP (Hyphen, also known as Aveugle or AVE), and KSR (Kinase Suppressor of RAS) (6, 7). The sterile ␣-motif (SAM) domain, present in both CNK and HYP, is essential for the ability of CNK/HYP/KSR to associate and for signals to transduce through the RAF-MEK-ERK cascade (6); see Fig. 1A for schematic of domain architecture.The structural characterization of SAM domains has revealed the basis by which some SAM domains engage in polymeric protein-protein interactions (8-14), and the basis by which certain SAM domains bind RNA (15-17). A characteristic constellation of basic residues in the sequence of some SAM domains is diagnostic for binding RNA hairpins in a loop sequence-dependent manner (18). In contrast, SAM domains that mediate polymeric proteinprotein interactions cannot be readily recognized from their primary sequence alone. Polymer formation by SAM domains in general arises from the interaction of two distinct surfaces on the SAM domain termed the midloop (ML) and end-helix (EH) surfaces (8). Repeating ML/EH interactions of adjacent SAM domains lead to polymer extension. SAM domain-mediated polymerization has been shown to underlie many aspects of biological function. For example, SAM domain-mediated polymerization is essential for long-range transcriptional repression by the polycomb group proteins (9). In the TEL transcriptional repressor, which is a common target of chromosomal translocations in several hematalogical malignancies, the N-terminal SA...

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The PI3K effector Arap3 interacts with the PI(3,4,5)P3 phosphatase SHIP2 in a SAM domain-dependent manner

Cited by 61 publications

References 36 publications

ARAP3 inhibits peritoneal dissemination of scirrhous gastric carcinoma cells by regulating cell adhesion and invasion

ARAP3 inhibits peritoneal dissemination of scirrhous gastric carcinoma cells by regulating cell adhesion and invasion

ARAP2 Signals through Arf6 and Rac1 to Control Focal Adhesion Morphology*

CNK and HYP form a discrete dimer by their SAM domains to mediate RAF kinase signaling

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