Phosphorylation-dependent Regulation of Connecdenn/DENND1 Guanine Nucleotide Exchange Factors

Kulasekaran, Gopinath; Nossova, Nadya; Marat, Andrea L.; Lund, Ingrid V.; Cremer, Christopher; Ioannou, Maria S.; McPherson, Peter S.

doi:10.1074/jbc.m115.636712

Cited by 22 publications

(20 citation statements)

References 33 publications

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“…An exceptional feature of DENND1A is its strong interaction with the surface of CCVs in vitro , even under conditions where clathrin is removed, suggesting a role after CCV formation . This strong association likely results from combined interactions between DENND1A and Rab35 itself, and with the AP‐2, accessory proteins, 14‐3‐3 proteins and phosphoinositides . Detailed TIRF‐microscopy‐based analysis recently revealed that DENND1A is loaded onto CCVs just after the scission of CCPs from the plasma membrane and a few seconds before Rab35 itself .…”

Section: Gefs and Gaps Control Tight Activation Of Rab35 On Newborn Ementioning

confidence: 99%

Rab35 GTPase: A Central Regulator of Phosphoinositides and F‐actin in Endocytic Recycling and Beyond

Klinkert

Échard

2016

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Rab35 is one of the first discovered members of the large Rab GTPase family, yet it received little attention for 10 years being considered merely as a Rab1-like GTPase. In 2006, Rab35 was recognized as a unique Rab GTPase localized both at the plasma membrane and on endosomes, playing essential roles in endocytic recycling and cytokinesis. Since then, Rab35 has become one of the most studied Rabs involved in a growing number of cellular functions, including endosomal trafficking, exosome release, phagocytosis, cell migration, immunological synapse formation and neurite outgrowth. Recently, Rab35 has been acknowledged as an oncogenic GTPase with activating mutations being found in cancer patients. In this review, we provide a comprehensive summary of known Rab35-dependent cellular functions and detail the few Rab35 effectors characterized so far. We also review how the Rab35 GTP/GDP cycle is regulated, and emphasize a newly discovered mechanism that controls its tight activation on newborn endosomes. We propose that the involvement of Rab35 in such diverse and apparently unrelated cellular functions can be explained by the central role of this GTPase in regulating phosphoinositides and F-actin, both on endosomes and at the plasma membrane.

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Section: Gefs and Gaps Control Tight Activation Of Rab35 On Newborn Ementioning

confidence: 99%

Rab35 GTPase: A Central Regulator of Phosphoinositides and F‐actin in Endocytic Recycling and Beyond

Klinkert

Échard

2016

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132

125

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“…For example, connecdenn1/2 are identified as GEFs for Rab35. Akt-mediated connecdenn 1/2 phosphorylation promotes the interaction of Rab35 and its GEF [ 77 ]. Unc-51-like kinases have been reported to phosphorylate DENND3 and upregulate its GEF activity toward Rab12.…”

Section: Introductionmentioning

confidence: 99%

Rab-mediated vesicle trafficking in cancer

2016

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A large group of small Rab GTPases which mediate secretory and endosomal membrane transport, as well as autophagosome biogenesis, are essential components of vesicle trafficking machinery. Specific Rab protein together with the cognate effectors coordinates the dynamics of trafficking pathway and determines the cargo proteins destination. Functional impairments of Rab proteins by mutations or post-translational modifications disrupting the regulatory network of vesicle trafficking have been implicated in tumorigenesis. Therefore, the vesicle transport regulators play essential roles in the mediation of cancer cell biology, including uncontrolled cell growth, invasion and metastasis. The context-dependent role of the same Rab to act as either an oncoprotein or tumor suppressor in different cancers is found. Such discrepancies may be due in part to the interaction of specific Rab protein with different effectors or cargos in various tumors. Here, we review recent advances in the roles of Rab GTPases in communicating with other effectors in tumor progression. In this review, we also emphasize dysregulation of Rab-mediated membrane delivery shifting normal cell behaviors toward malignancy. Thus, recovery of the dysregulated vesicle trafficking systems in cancer cells may provide future directions for potential strategy to restrain tumor progression.

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“…Some Rab35 GEFs, such as connecdenn 1 and 2, are activated by Akt-dependent phosphorylation [Kulasekaran et al, 2015]. On the other hand, in HEK-293E and NIH-3T3 cells, Rab35 activates Akt upstream of PDK1, mTORC2, and, even, PI3K [Wheeler et al, 2015], indicating that Rab35 activation occurs upstream of the PI3K-Akt pathway.…”

Section: Rab35mentioning

confidence: 99%

Rab GTPase signaling in neurite outgrowth and axon specification

2016

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Neurons are highly polarized cells that contain specialized subcellular domains involved in information transmission in the nervous system. Specifically, the somatodendritic compartment receives neuronal inputs while the axons convey information through the synapse. The establishment of asymmetric domains requires a specific delivery of components, including organelles, proteins, and membrane. The Rab family of small GTPases plays an essential role in membrane trafficking. Signaling cascades triggered by extrinsic and intrinsic factors tightly regulate Rab functions in cells, with Rab protein activation depending on GDP/GTP binding to establish a binary mode of action. This review summarizes the contributions of several Rab family members involved in trans-Golgi, early/late endosomes, and recycling endosomes during neurite development and axonal outgrowth. The regulation of some Rabs by guanine exchanging factors and GTPase activating proteins will also be addressed. Finally, discussion will be provided on how specific effector-mediated Rab activation modifies several molecules essential to neuronal differentiation. V C 2016 Wiley Periodicals, Inc.

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Phosphorylation-dependent Regulation of Connecdenn/DENND1 Guanine Nucleotide Exchange Factors

Cited by 22 publications

References 33 publications

Rab35 GTPase: A Central Regulator of Phosphoinositides and F‐actin in Endocytic Recycling and Beyond

Rab35 GTPase: A Central Regulator of Phosphoinositides and F‐actin in Endocytic Recycling and Beyond

Rab-mediated vesicle trafficking in cancer

Rab GTPase signaling in neurite outgrowth and axon specification

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