DIP (mDia interacting protein) is a key molecule regulating Rho and Rac in a Src-dependent manner

Meng, Wenxiang; Numazaki, Mitsuko; Takeuchi, Kumiko; Uchibori, Yoshiari; Ando‐Akatsuka, Yuhko; Tominaga, Makoto; Tominaga, Tomoko

doi:10.1038/sj.emboj.7600095

Cited by 65 publications

(80 citation statements)

References 33 publications

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“…This regulation of the myosin heavy chain differs from the usual regulation through the light chain ( Conti and Adelstein, 2008 ). Talin, ␣ -actinin, and the actin nucleator mDia1 also appeared regulated (to a lesser extent), and all have been implicated previously in phagocytosis (respectively: [( Turner et al, 1989 ;Greenberg et al, 1990 ); ( Crowley and Horwitz, 1995 ;Izaguirre et al, 1999 ); ( Meng et al, 2004 ;Brandt et al, 2007 )]). Although phospho-paxillin was downregulated in our imaging studies, it was not prominent in our immunoblots and was unaffected by blebbistatin, which otherwise mimicked CD47 ' s inhibitory effects ( Figs.…”

Section: Phosphotyrosine Activation Of Nmm Iia In Phagocytosismentioning

confidence: 97%

“…8 C , bottom). Additional cytoskeletal proteins that were detected in the macrophages and might be targeted in the CD47-SIRP ␣ phosphotyrosine pathway include Talin-1 ( Turner et al, 1989 ;Greenberg et al, 1990 ), mDIA1 ( Meng et al, 2004 ), and ␣ -actinin ( Crowley and Horwitz, 1995 ;Izaguirre et al, 1999 ). Capabilities of MS to identify phosphotyrosine are currently limited, as here, by low sequence coverage and sub-stoichiometric phosphorylation ( McLachlin and Chait, 2001 ).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells

Tsai¹,

Discher²

2008

J Exp Med

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(2008). Inhibition of "self " engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. Retrieved from http://repository.upenn.edu/cbe_papers/108Inhibition of "self " engulfment through deactivation of myosin-II at the phagocytic synapse between human cells AbstractPhagocytosis of foreign cells or particles by macrophages is a rapid process that is inefficient when faced with "self " cells that display CD47-although signaling mechanisms in self-recognition have remained largely unknown. With human macrophages, we show the phagocytic synapse at cell contacts involves a basal level of actin-driven phagocytosis that, in the absence of species-specific CD47 signaling, is made more efficient by phospho-activated myosin. We use "foreign" sheep red blood cells (RBCs) together with CD47-blocked, antibody-opsonized human RBCs in order to visualize synaptic accumulation of phosphotyrosine, paxillin, Factin, and the major motor isoform, nonmuscle myosin-IIA. When CD47 is functional, the macrophage counter-receptor and phosphatase-activator SIRPα localizes to the synapse, suppressing accumulation of phosphotyrosine and myosin without affecting F-actin. On both RBCs and microbeads, human CD47 potently inhibits phagocytosis as does direct inhibition of myosin. CD47-SIRPα interaction initiates a dephosphorylation cascade directed in part at phosphotyrosine in myosin. A point mutation turns off this motor's contribution to phagocytosis, suggesting that self-recognition inhibits contractile engulfment. Comments

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Section: Phosphotyrosine Activation Of Nmm Iia In Phagocytosismentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells

Tsai¹,

Discher²

2008

J Exp Med

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“…Activated mDia1 and mDia2 induce signaling downstream of Rho GTPases along with Src (Tominaga et al, 2000). More recently, it was shown that mDia-interacting protein (DIP) is phosphorylated by Src following EGF stimulation (Meng et al, 2004). Phosphorylated DIP in turn associates with p190RhoGAP and Vav2.…”

Section: Ubiquitinationmentioning

confidence: 99%

The interplay between Src family kinases and receptor tyrosine kinases

2004

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Src family tyrosine kinases (SFKs) are involved in a diverse array of physiological processes, as highlighted in this review. An overview of how SFKs interact with, and participate in signaling from, receptor tyrosine kinases (RTKs) is discussed. And also, how SFKs are activated by RTKs, and how SFKs, in turn, can activate RTKs, as well as how SFKs can promote signaling from growth factor receptors in a number of ways including participation in signaling pathways required for DNA synthesis, control of receptor turnover, actin cytoskeleton rearrangements and motility, and survival are discussed.

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“…cDNAs encoding N-terminal FLAG-tagged human ␣-and ␤-PIX were subcloned into the mammalian expression vector pCMV2 (Sigma-Aldrich). Mammalian expression vectors pCIneoFLAG-ALS2_L (20), pCS2-Myc-Tiam1 (21), and pcDNA3-Myc-Vav2 (22) were kindly provided by Shinji Hadano and Joh-E Ikeda (Tokai University), Haruhiko Sugimura (Hamamatsu University School of Medicine), and Tomoko Tominaga (Okazaki National Research Institutes), respectively. cDNAs encoding N-terminal FLAG-tagged GABARAP, N-terminal FLAG-and C-terminal V5-tagged GABARAP (designated GABARAP117), and N-terminal FLAG-and C-terminal V5-tagged GABARAP-(1-115) (designated GABARAP115) were subcloned into pCMV2.…”

Section: Methodsmentioning

confidence: 99%

Role of the Guanine Nucleotide Exchange Factor Ost in Negative Regulation of Receptor Endocytosis by the Small GTPase Rac1

Ieguchi

Ueda

Kataoka

et al. 2007

Journal of Biological Chemistry

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The Rho family of GTPases has been implicated in the regulation of intracellular vesicle trafficking. Here, we investigated the mechanism underlying the negative regulation of clathrinmediated endocytosis of cell surface receptors mediated by the Rho family protein Rac1. Contrary to previous reports, only the activated mutant of Rac1, but not other Rho family members including RhoA and Cdc42, suppressed internalization of the transferrin receptor. On the other hand, down-regulation of Rac1 expression by RNA interference resulted in enhanced receptor internalization, suggesting that endogenous Rac1 in fact functions as a negative regulator. We identified a guanine nucleotide exchange factor splice variant designated Ost-III, which contains a unique C-terminal region including an Src homology 3 domain, as a regulator of Rac1 involved in the inhibition of receptor endocytosis. In contrast, other splice variants Ost-I and Ost-II exerted virtually no effect on receptor endocytosis. We also examined subcellular localization of synaptojanin 2, a putative Rac1 effector implicated in negative regulation of receptor endocytosis. Each Ost splice variant induced distinct subcellular localization of synaptojanin 2, depending on Rac1 activation. Furthermore, we isolated ␥-aminobutyric acid type A receptor-associated protein (GABARAP) as a protein that binds to the C-terminal region of Ost-III. When ectopically expressed, GABARAP was co-localized with Ost-III and potently suppressed the Ost-III-dependent Rac1 activation and the inhibition of receptor endocytosis. Lipid modification of GABARAP was necessary for the suppression of Ost-III. These results are discussed in terms of subcellular region-specific regulation of the Rac1-dependent signaling pathway that negatively regulates clathrin-mediated endocytosis.In eukaryotic cells the continuous uptake of essential nutrients such as iron-laden transferrin and the cholesterol-laden low density lipoprotein is carried out through clathrin-mediated endocytosis of their respective receptors. Additionally, clathrin-mediated endocytosis is the main pathway for internalization of various growth factor receptors. It mediates rapid clearance and down-regulation of activated receptors, thereby regulating the levels of cell surface receptors. The receptorligand complex is internalized into a clathrin-coated pit that is formed through the action of the adaptor protein complex AP-2 and a variety of accessory proteins, including AP180, Eps15, amphiphysin, and epsin. Subsequently, clathrin-coated pits pinch off to form clathrin-coated vesicles that are encapsulated by a polygonal clathrin coat and carry concentrated receptor-ligand complexes into the cell. Clathrin-coated vesicle fission is driven by the GTPase dynamin. The coat of clathrin-coated vesicles is removed shortly after the vesicle forms, generating an early endosome. This endosome fuses with a late endosome, where the low pH causes the dissociation of the receptor-ligand complex. A receptor-rich region buds off to form a separate ve...

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DIP (mDia interacting protein) is a key molecule regulating Rho and Rac in a Src-dependent manner

Cited by 65 publications

References 33 publications

Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells

Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells

The interplay between Src family kinases and receptor tyrosine kinases

Role of the Guanine Nucleotide Exchange Factor Ost in Negative Regulation of Receptor Endocytosis by the Small GTPase Rac1

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