The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain

Xu, Zhen; Gakhar, Lokesh; Bain, Fletcher E; Spies, Maria; Fuentes, Ernesto J.

doi:10.1074/jbc.m117.799114

Cited by 19 publications

(16 citation statements)

References 78 publications

(83 reference statements)

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“…Structurally, Tiam-1 is composed of a myristoylation sequence, coiled-coil region, PEST, N-terminal and C-terminal PH, extended, Ras binding, PSD-95/DlgA/ZO-1, and DH domains. Similar to other GEFs, Tiam1 is auto-inhibited by its N-terminal PH domain coiled-coiled extension, blocking its GEF activity (Xu Z. et al, 2017). Tiam1 is regulated through phosphorylation, which localizes Tiam1 to the membrane to interact with cell surface receptors (Boissier, 2013).…”

Section: Targeting Tiam1mentioning

confidence: 99%

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maldonado

Medina

Velázquez

et al. 2020

Front. Cell Dev. Biol.

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The Rho family GTPases Rho, Rac, and Cdc42 have emerged as key players in cancer metastasis, due to their essential roles in regulating cell division and actin cytoskeletal rearrangements; and thus, cell growth, migration/invasion, polarity, and adhesion. This review will focus on the close homologs Rac and Cdc42, which have been established as drivers of metastasis and therapy resistance in multiple cancer types. Rac and Cdc42 are often dysregulated in cancer due to hyperactivation by guanine nucleotide exchange factors (GEFs), belonging to both the diffuse B-cell lymphoma (Dbl) and dedicator of cytokinesis (DOCK) families. Rac/Cdc42 GEFs are activated by a myriad of oncogenic cell surface receptors, such as growth factor receptors, G-protein coupled receptors, cytokine receptors, and integrins; consequently, a number of Rac/Cdc42 GEFs have been implicated in metastatic cancer. Hence, inhibiting GEF-mediated Rac/Cdc42 activation represents a promising strategy for targeted metastatic cancer therapy. Herein, we focus on the role of oncogenic Rac/Cdc42 GEFs and discuss the recent advancements in the development of Rac and Cdc42 GEF-interacting inhibitors as targeted therapy for metastatic cancer, as well as their potential for overcoming cancer therapy resistance.

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Section: Targeting Tiam1mentioning

confidence: 99%

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maldonado

Medina

Velázquez

et al. 2020

Front. Cell Dev. Biol.

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“…Thus, they are poised to mediate cell-autonomous and -nonautonomous functions of Par3 in PCP signaling. It has been reported that the GEF activity of Tiam1 and Trio is autoinhibited through intramolecular interactions (36,37). As a scaffold protein, Par3 may mediate membrane translocation and release of autoinhibition of Tiam1 and Trio to activate Rac signaling in both hair cells and supporting cells.…”

Section: Discussionmentioning

confidence: 99%

Par3 is essential for the establishment of planar cell polarity of inner ear hair cells

Malt

Dailey

Holbrook-Rasmussen

et al. 2019

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

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In the inner ear sensory epithelia, stereociliary hair bundles atop sensory hair cells are mechanosensory apparatus with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level, intercellular planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 is essential for planar polarization of hair cells. Par3 deletion in the inner ear disrupted cochlear outgrowth, hair bundle orientation, kinocilium positioning, and basal body planar polarity, accompanied by defects in the organization and cortical attachment of hair cell microtubules. Genetic mosaic analysis revealed that Par3 functions both cell-autonomously and cellnonautonomously to regulate kinocilium positioning and hair bundle orientation. At the tissue level, intercellular PCP signaling regulates the asymmetric localization of Par3, which in turn maintains the asymmetric localization of the core PCP protein Vangl2. Mechanistically, Par3 interacts with and regulates the localization of Tiam1 and Trio, which are guanine nucleotide exchange factors (GEFs) for Rac, thereby stimulating Rac-Pak signaling. Finally, constitutively active Rac1 rescued the PCP defects in Par3-deficient cochleae. Thus, a Par3-GEF-Rac axis mediates both tissue-level and hair cell-intrinsic PCP signaling.planar cell polarity | stereocilia | hair cell | Par3 | microtubule

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“…GEF activities of the full-length proteins can be influenced by auto-inhibitory domains 33 , protein-protein interactions and by phosphorylation of specific residues 34 . Although FL GEF studies may appear physiologically the most relevant, the use of isolated GEF domains limits complexity.…”

Section: Discussionmentioning

confidence: 99%

Selectivity of Guanine Nucleotide Exchange Factor-mediated Cdc42 activation in primary human endothelial cells

Chertkova

et al. 2019

Preprint

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The Rho GTPase family is involved in actin dynamics and regulates the barrier function of the endothelium. One of the main barrier-promoting Rho GTPases is Cdc42, also known as cell division control protein 42 homolog. Currently, regulation of Cdc42-based signaling networks in endothelial cells (ECs) lack molecular details. To examine these, we focused on a subset of 15 Rho guanine nucleotide exchange factors (GEFs), which are expressed in the endothelium.By performing single cell FRET measurements with Rho GTPase biosensors in primary human ECs, we monitored GEF efficiency towards Cdc42 and Rac1. A new, single cell-based analysis was developed and used to enable the quantitative comparison of cellular activities of the fulllength GEFs. Our data reveal a specific GEF dependent activation profile, with most efficient Cdc42 activation induced by PLEKHG2, FGD1, PLEKHG1 and pRex1 and the highest selectivity for FGD1. Additionally, we generated truncated GEF constructs that comprise only the catalytic dbl homology (DH) domain or together with the adjacent pleckstrin homology domain (DHPH). The DH domain by itself did not activate Cdc42, whereas the DHPH domain of ITSN1, ITSN2 and PLEKHG1 showed activity towards Cdc42. Together, our study characterized endothelial GEFs that may activate Cdc42, which will be of great value for the field of vascular biology.

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The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain

Cited by 19 publications

References 78 publications

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Par3 is essential for the establishment of planar cell polarity of inner ear hair cells

Selectivity of Guanine Nucleotide Exchange Factor-mediated Cdc42 activation in primary human endothelial cells

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