Rac GTPases in Hematological Malignancies

Emerging evidence suggests that crosstalk between hematologic tumor cells and the tumor microenvironment contributes to leukemia and lymphoma cell migration, survival, and proliferation. The supportive tumor cell-microenvironment interactions and the resulting cellular processes require adaptations and modulations of the cytoskeleton. The Rac subfamily of the Rho family GTPases includes key regulators of the cytoskeleton, with essential functions in both normal and transformed leukocytes. Rac proteins function downstream of receptor tyrosine kinases, chemokine receptors, and integrins, orchestrating a multitude of signals arising from the microenvironment. As such, it is not surprising that deregulation of Rac expression and activation plays a role in the development and progression of hematological malignancies. In this review, we will give an overview of the specific contribution of the deregulation of Rac GTPases in hematologic malignancies.

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Integrin regulation of membrane domain trafficking and Rac targeting

Biochemical Society Transactions ◽

10.1042/bst0330609 ◽

2005 ◽

Vol 33 (4) ◽

pp. 609-613 ◽

Cited By ~ 21

Author(s):

A. Grande-García ◽

A. Echarri ◽

M.A. Del Pozo

Keyword(s):

Cell Growth ◽

Binding Sites ◽

Cell Cycle Progression ◽

Membrane Microdomains ◽

Cycle Progression ◽

Cellular Processes ◽

Rho Family Gtpases ◽

Rho Family ◽

And Migration ◽

Integrin Regulation

Integrins are crucial regulators of essential cellular processes such as gene expression, cell proliferation and migration. Alteration of these processes is central to tumourigenesis. Integrin signals mediate anchorage dependence of cell growth, while growth of cancer cells is anchorage-independent. Integrins critically regulate Rho family GTPases, that are also involved in cell-cycle progression and oncogenesis. In addition to their effect on GTP loading, integrins independently control the translocation of GTP-bound Rac to the plasma membrane. This step is essential for Rac binding to effectors. Integrins increase membrane affinity for Rac, leading to RhoGDI dissociation and effector coupling locally, in the vicinity of activated/bound integrins. Integrin-regulated Rac binding sites are within CEMMs (cholesterol-enriched membrane microdomains). Integrins control Rac signalling by preventing the internalization of its binding sites in CEMMs. Integrin regulation of signalling pathways initiated in CEMMs may be important for the spatial control of cell migration and anchorage dependence of cell growth.

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Regulation of class IA PI3Ks

Biochemical Society Transactions ◽

10.1042/bst0350242 ◽

2007 ◽

Vol 35 (2) ◽

pp. 242-244 ◽

Cited By ~ 33

Author(s):

H. Wu ◽

Y. Yan ◽

J.M. Backer

Keyword(s):

Tyrosine Kinases ◽

Regulatory Subunit ◽

Sh2 Domains ◽

Src Homology 2 ◽

Pi3k Activity ◽

Wide Range ◽

Rho Family Gtpases ◽

Src Homology ◽

Rho Family

Class IA PI3Ks (phosphoinositide 3-kinases) regulate a wide range of cellular responses through the production of PI(3,4,5)P3 (phosphatidylinositol 3,4,5-trisphosphate) in cellular membranes. They are activated by receptor tyrosine kinases, by Ras and Rho family GTPases, and in some cases by Gβγ subunits from trimeric G-proteins. Crystallographic studies on the related class IB PI3Kγ, and biochemical and structural studies on the class IA PI3Ks, have led to new insights into how these critical enzymes are regulated in normal cells and how mutations can lead to their constitutive activation in transformed cells. The present paper will discuss recent studies on the regulation of class I (p85/p110) PI3Ks, with a focus on the role of SH2 domains (Src homology 2 domains) in the p85 regulatory subunit in modulating PI3K activity.

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Abl tyrosine kinases modulate cadherin-dependent adhesion upstream and downstream of Rho family GTPases

Cell Cycle ◽

10.4161/cc.7.4.5452 ◽

2008 ◽

Vol 7 (4) ◽

pp. 444-448 ◽

Cited By ~ 38

Author(s):

Nicole L. Zandy ◽

Ann Marie Pendergast

Keyword(s):

Tyrosine Kinases ◽

Rho Family Gtpases ◽

Rho Family

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The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization.

Molecular and Cellular Biology ◽

10.1128/mcb.17.4.2247 ◽

1997 ◽

Vol 17 (4) ◽

pp. 2247-2256 ◽

Cited By ~ 141

Author(s):

S Vincent ◽

J Settleman

Keyword(s):

Protein Kinases ◽

Kinase Activity ◽

Rho Kinase ◽

Close Relative ◽

Rho Proteins ◽

Cellular Processes ◽

Rac Gtpases ◽

Downstream Effector ◽

Rho Family Gtpases

The Ras-related Rho family GTPases mediate signal transduction pathways that regulate a variety of cellular processes. Like Ras, the Rho proteins (which include Rho, Rac, and CDC42) interact directly with protein kinases, which are likely to serve as downstream effector targets of the activated GTPase. Activated RhoA has recently been reported to interact directly with several protein kinases, p120 PKN, p150 ROK alpha and -beta, p160 ROCK, and p164 Rho kinase. Here, we describe the purification of a novel Rho-associated kinase, p140, which appears to be the major Rho-associated kinase activity in most tissues. Peptide microsequencing revealed that p140 is probably identical to the previously reported PRK2 kinase, a close relative of PKN. However, unlike the previously described Rho-binding kinases, which are Rho specific, p140 associates with Rac as well as Rho. Moreover, the interaction of p140 with Rho in vitro is nucleotide independent, whereas the interaction with Rac is completely GTP dependent. The association of p140 with either GTPase promotes kinase activity substantially, and expression of a kinase-deficient form of p140 in microinjected fibroblasts disrupts actin stress fibers. These results indicate that p140 may be a shared kinase target of both Rho and Rac GTPases that mediates their effects on rearrangements of the actin cytoskeleton.

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RHO Family GTPases in the Biology of Lymphoma

Cells ◽

10.3390/cells8070646 ◽

2019 ◽

Vol 8 (7) ◽

pp. 646 ◽

Cited By ~ 2

Author(s):

Voena ◽

Chiarle

Keyword(s):

Rho Gtpases ◽

Intracellular Signaling ◽

Human Cancer ◽

Loss Of Function ◽

Cellular Processes ◽

Ras Gtpase ◽

Rho Family Gtpases ◽

Ras Family ◽

Human Lymphoma ◽

Rho Family

RHO GTPases are a class of small molecules involved in the regulation of several cellular processes that belong to the RAS GTPase superfamily. The RHO family of GTPases includes several members that are further divided into two different groups: typical and atypical. Both typical and atypical RHO GTPases are critical transducers of intracellular signaling and have been linked to human cancer. Significantly, both gain-of-function and loss-of-function mutations have been described in human tumors with contradicting roles depending on the cell context. The RAS family of GTPases that also belong to the RAS GTPase superfamily like the RHO GTPases, includes arguably the most frequently mutated genes in human cancers (K-RAS, N-RAS, and H-RAS) but has been extensively described elsewhere. This review focuses on the role of RHO family GTPases in human lymphoma initiation and progression.

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Caspase 3-Mediated Inactivation of Rac GTPases Promotes Drug-Induced Apoptosis in Human Lymphoma Cells

Molecular and Cellular Biology ◽

10.1128/mcb.23.16.5716-5725.2003 ◽

2003 ◽

Vol 23 (16) ◽

pp. 5716-5725 ◽

Cited By ~ 27

Author(s):

Baolin Zhang ◽

Yaqin Zhang ◽

Emily Shacter

Keyword(s):

Caspase 3 ◽

Cell Transformation ◽

Lymphoma Cells ◽

Drug Induced ◽

Effector Functions ◽

Rac Gtpases ◽

Rho Family Gtpases ◽

Human Lymphoma ◽

Rho Family ◽

Induced Apoptosis

ABSTRACT The Rac members of the Rho family GTPases control signaling pathways that regulate diverse cellular activities, including cytoskeletal organization, gene transcription, and cell transformation. Rac is implicated in apoptosis, but little is known about the mechanism by which it responds to apoptotic stimuli. Here we demonstrate that endogenous Rac GTPases are caspase 3 substrates that are cleaved in human lymphoma cells during drug-induced apoptosis. Cleavage of Rac1 occurs at two unconventional caspase 3 sites, VVGD11/G and VMVD47/G, and results in inactivation of the GTPase and effector functions of the protein (binding to the p21-activated protein kinase PAK1). Expression of caspase 3-resistant Rac1 mutants in the cells suppresses drug-induced apoptosis. Thus, proteolytic inactivation of Rac GTPases represents a novel, irreversible mechanism of Rac downregulation that allows maximal cell death following drug treatment.

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