The Rac GTPase in Cancer: From Old Concepts to New Paradigms

Kazanietz, Marcelo G.; Caloca, María-José

doi:10.1158/0008-5472.can-17-1456

Cited by 153 publications

(146 citation statements)

References 62 publications

(82 reference statements)

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“…Little is known about the detailed mechanisms of Cdc42 and Rac1 in actin polymerization (43,44), although progress is being made (45). Their functions differ; Cdc42 enhances filopodia (containing parallel bundles of filamentous (F)-actin) formation, while Rac1 promotes lamellipodia (17,46,47).…”

Section: Discussionmentioning

confidence: 99%

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2

Ozdemir

Jang

Gürsoy

et al. 2018

Journal of Biological Chemistry

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IQ motif-containing GTPase-activating protein (IQGAP) scaffolding proteins play central roles in cell-cell adhesion, polarity, and motility. The Rho GTPases Cdc42 and Rac1, in their GTPbound active forms, interact with all three human IQGAPs. The IQGAP-Cdc42 interaction promotes metastasis by enhancing actin polymerization. However, despite their high sequence identity, Cdc42 and Rac1 differ in their interactions with IQGAP. Two Cdc42 molecules can bind to the Exdomain and the RasGAP site of the GTPaseactivating protein (GAP)-related domain (GRD) of IQGAP and promote IQGAP dimerization. Only one Rac1 molecule might bind to the RasGAP site of GRD and may not facilitate the dimerization, and the exact mechanism of Cdc42 and Rac1 binding to IQGAP is unclear. Using all-atom molecular dynamics simulations, site-directed mutagenesis, and Western blotting, we unraveled the detailed mechanisms of Cdc42 and Rac1 interactions with IQGAP2. We observed that Cdc42 binding to the Ex-domain of GRD of IQGAP2 (GRD2) releases the Ex-domain at the C-terminal region of GRD2, facilitating IQGAP2 dimerization. Cdc42 binding to the Ex-domain promoted allosteric changes in the RasGAP site, providing a binding site for the second Cdc42 in the RasGAP site. Of note, the Cdc42 "insert loop" was important for the interaction of the first Cdc42 with the Ex-domain. By contrast, differences in Rac1 insert loop sequence and structure precluded its interaction with the Ex-domain. Rac1 could bind only to the RasGAP site of apo-GRD2 and could not facilitate IQGAP2 dimerization. Our detailed mechanistic insights help decipher how Cdc42 can stimulate actin polymerization in metastasis.The Rho GTPase family is a subfamily of the Ras GTPase superfamily. Rho GTPases regulate multiple cellular processes such as growth, survival, cell invasion, cell motility and vesicle trafficking by interacting with effector molecules (1-4). To date, the mammalian Rho GTPase family includes 22 members; Cdc42, Rac1, and RhoA are the most studied among them (5).Rho GTPases are distinguished from other GTPases by the presence of an "insert loop" which is rich in charged residues in an α-helical motif (Fig. http://www.jbc.org/cgi

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Section: Discussionmentioning

confidence: 99%

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2

Ozdemir

Jang

Gürsoy

et al. 2018

Journal of Biological Chemistry

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“…This last step leads to a conformational change in Rac that favors its interaction with downstream effectors at specific intracellular compartments. Conversely, GAPs are responsible for Rac inactivation by stimulating the intrinsic GTPase activity and accelerating the rate of GTP hydrolysis (1–5). …”

Section: Regulation Of Rac Activity: Nucleotide Binding Post-translamentioning

confidence: 99%

“…Rac1 overexpression and/or hyperactivation have been reported in various cancers, including prostate, testicular, ovarian, lung, and gastric cancer (5, 25–29). In some cases, high expression of Rac1 has been associated with the expression epithelial-to-mesenchymal transition (EMT) markers and correlates with poor patient prognosis.…”

Section: Aberrant Rac Expression and Activity In Human Cancermentioning

confidence: 99%

“…In cancer, Rac-GEF deregulation occurs as a consequence of overexpression, activating mutations/deletions, and/or excessive upstream inputs (1, 3, 5). There are more than 80 Rho-family GEFs in the genome that can be structurally divided into two classes.…”

Section: Aberrant Rac Inputs and Outputs In Human Cancermentioning

confidence: 99%

“…Individual Rho family members play distinctive roles in normal physiological processes and development, and have been widely associated with a number of diseases. In particular, Rac GTPases (Rac1, Rac2, and Rac3) have been recognized as important nodes in signaling networks that control malignant transformation and the metastatic dissemination of cancer cells (1–5). Dissecting the molecular mechanisms controlling the activity of Rac and other related GTPases, identifying their regulators and effectors, and establishing their alterations in cancer cells have become a significant goal in the field of cancer research.…”

Section: Introductionmentioning

confidence: 99%

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The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic

Casado‐Medrano

Baker

López‐Haber

et al. 2018

Biochemical Society Transactions

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The family of Rho GTPases are involved in the dynamic control of cytoskeleton reorganization and other fundamental cellular functions, including growth, motility, and survival. Rac1, one of the best characterized Rho GTPases, is an established effector of receptors and an important node in signaling networks crucial for tumorigenesis and metastasis. Rac1 hyperactivation is common in human cancer, and could be the consequence of overexpression, abnormal upstream inputs, deregulated degradation, and/or anomalous intracellular localization. More recently, cancer associated gain-of-function mutations in Rac1 have been identified which contribute to tumor phenotypes and confer resistance to targeted therapies. Deregulated expression/activity of Rac Guanine nucleotide Exchange Factors (GEFs) responsible for Rac activation has been largely associated to a metastatic phenotype and drug resistance. Translating our extensive knowledge in Rac pathway biochemistry into a clinical setting still remains a major challenge, nonetheless remarkable opportunities for cancer therapeutics arise from promising lead compounds targeting Rac and its effectors.

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Stretching Induces Overexpression of RhoA and Rac1 GTPases in Breast Cancer Cells

2019

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and progesterone have an established role in undifferentiated breast cancer. While the activation of PI3K/AKT and JUN/ MAPK pathways may suppress breast cancer development. Interaction between these pathways is again a factor to consider. It is known that PI3K/AKT pathway is targeted in estrogen positive breast cancer for therapeutic applications as this pathway is activated by the 17 beta-estradiol. [2] Furthermore, MAP kinase receptors crosstalk with estrogen receptors to enhance the estrogen mediated signaling. [3] These pathways receive signals from extracellular signals via the cellular receptors and are responsible for the intracellular and cellular changes. It is now widely accepted that extracellular physical factors also play a significant role in cellular undifferentiation and mutation of malignant cells. The Rho-GTPase signaling pathway regulates cellular morphology and intracellular interaction, therefore, attracted interest in cancer biology research. [4] Rho GTPases belong to a family of regulatory small guanosine triphosphate (GTP) binding proteins in the Ras superfamily. They are small molecules of 21-25 kDa that share structural homology and when activated bind to GTP. The studies carried out in the early 1990s indicated that the Rho proteins regulate cell morphology through actin cytoskeleton. [5] However, recent studies show that they also influence gene expression, cell proliferation, and survival [6] ; all cellular functions that play a crucial role in carcinogenesis. [7] Rho GTPases are responsible for actin cytoskeleton rearrangement after the extracellular matrix (ECM) mechanical properties variations. Mammals have 22 Rho GTPases and most of them affect the cell morphology. The primary mechanism of the Rho GTPases action is the change in the membrane-associated actin cytoskeleton. The widely investigated members of this family are RhoA, Rac1, and Cdc42. [8] RhoA, the first member of this family, is activated by mechanical stress, ROCK, or mammalian Diaphanous. [9] Rac1, another member of the family, is also activated by mechanical stimuli and affects cyclic stretchinginduced cells and stress fibers reorientation. However, different Rho-Guanine nucleotide exchange factors and Rho-GTPaseactivating proteins are regulated during mechanotransduction. These Rho-GEFs and Rho-GAPs are actively involved in actin cytoskeletal remodeling in mechano-responses. [10] Though reported as both oncogenic and tumor suppressors, RHO GTPases are associated with the acquirement of malignant Rho GTPases are well known for regulating cell morphology and intracellular interactions. They can either be oncogenic or tumor suppressors. However, these proteins are associated with the acquirement of malignant features by cancer cells. It has been reported that the overexpression of protein markers of Rho family members such as RhoA and Rac1 is linked with carcinogenesis and the progression of a variety of human tumors. In this paper, the expression of RhoA and Rac1 activity in various types of breast cancers cell line...

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The Rac GTPase in Cancer: From Old Concepts to New Paradigms

Cited by 153 publications

References 62 publications

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2

The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic

Stretching Induces Overexpression of RhoA and Rac1 GTPases in Breast Cancer Cells

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