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Last update 08 May 2025

PREX2

Last update 08 May 2025

Basic Info

Synonyms

DEP domain-containing protein 2, DEP.2, DEPDC2

+ [7]

Introduction

Functions as a RAC1 guanine nucleotide exchange factor (GEF), activating Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. Mediates the activation of RAC1 in a PI3K-dependent manner. May be an important mediator of Rac signaling, acting directly downstream of both G protein-coupled receptors and phosphoinositide 3-kinase.

Drugs associated with PREX2

US20220409704

Patent Mining

Target

PREX2

Mechanism-

Active Org.

Kaohsiung Medical University

Originator Org.

Kaohsiung Medical University

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with PREX2

100 Translational Medicine associated with PREX2

0 Patents (Medical) associated with PREX2

581

Literatures (Medical) associated with PREX2

17 Feb 2025·Cancer Research

Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma

Article

Author: Barry, Simon T. ; Campbell, Andrew D. ; Hornigold, David C. ; Munro, Alison F. ; Vlahov, Nikola ; Ford, Catriona A. ; Dunne, Philip D. ; Welch, Heidi C.E. ; Carragher, Neil O. ; Dawson, John C. ; Nixon, Colin ; Pavet, Valeria ; Gilroy, Kathryn ; Koludrovic, Dana ; Downward, Julian ; Foth, Mona ; Bull, Courtney ; Tsonou, Elpida ; Serrels, Bryan ; Centeno, Patricia P. ; Sansom, Owen J. ; Sphyris, Nathalie

AbstractMetastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression. Here, we used genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. Although PREX2 was dispensable for the initiation and progression of melanoma, its loss conferred sensitivity to clinically relevant therapeutics targeting the MAPK pathway. Importantly, genetic and pharmacologic targeting of PI3Kβ phenocopied PREX2 deficiency, sensitizing model systems to therapy. These data reveal a druggable PREX2/RAC1/PI3Kβ signaling axis in BRAF-mutant melanoma that could be exploited clinically.Significance: Cotargeting the MAPK and the PREX2/RAC1/PI3Kβ pathways has remarkable efficacy and outperforms monotherapy MAPK inhibition in BRAF-mutant melanoma, supporting the potential of this combination therapy for treating metastatic melanoma.

01 Feb 2025·Cell Reports

Inositol polyphosphate multikinase regulates Th1 and Th17 cell differentiation by controlling Akt-mTOR signaling

Article

Author: Jeong, Hyun-Woo ; Park, Seung Ju ; Kim, Mingyo ; Seong, Rho Hyun ; Kim, Wooseob ; Kim, Seyun ; Kim, Hyo Dam ; Lim, Jongbu ; Kim, Dongeon ; Lee, Seung-Hyo ; Min, Hyungyu ; Hong, Sehoon ; Kim, Sang-Gyu ; Yuk, Chae Min

Activated proinflammatory T helper (Th) cells, including Th1 and Th17 cells, drive immune responses against pathogens and contribute to autoimmune diseases. We show that the expression of inositol polyphosphate multikinase (IPMK), an enzyme essential for inositol phosphate metabolism, is highly induced in Th1 and Th17 subsets. Deletion of IPMK in CD4⁺ T cells leads to diminished Th1- and Th17-mediated responses, reducing resistance to Leishmania major and attenuating experimental autoimmune encephalomyelitis. IPMK-deficient CD4⁺ T cells show impaired activation and Th17 differentiation, linked to the decreased activation of Akt, mTOR, and STAT3. Mechanistically, IPMK functions as a phosphatidylinositol 3-kinase to regulate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P₃) production, promoting T cell activation and effector functions. In IPMK-deficient CD4⁺ T cells, T cell receptor-stimulated PtdIns(3,4,5)P₃ generation is abolished by wortmannin, suggesting IPMK acts in a wortmannin-sensitive manner. These findings establish IPMK as a critical regulator of Th1 and Th17 differentiation, underscoring its role in maintaining immune homeostasis.

01 Sep 2024·Molecular Biology of the Cell

The LCLAT1/LYCAT acyltransferase is required for EGF-mediated phosphatidylinositol-3,4,5-trisphosphate generation and Akt signaling

Article

Author: Fu, Norman J. ; Camardi, Cristina ; Bone, Leslie N. ; Salmena, Leonardo ; Anderson, Karen E. ; Stephens, Len R. ; Awadeh, Yasmin ; Zhang, Kai ; Orofiamma, Laura A. ; Botelho, Roberto J. ; Antonescu, Costin N. ; Hoque, Jafarul ; Hawkins, Phillip T. ; Lee, Daniel K. C. ; Chan, Victoria ; Chow, Jonathan T. S.

Receptor tyrosine kinases such as EGF receptor (EGFR) stimulate phosphoinositide 3 kinases to convert phosphatidylinositol-4,5-bisphosophate [PtdIns(4,5)P2] into phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3]. PtdIns(3,4,5)P3 then remodels actin and gene expression, and boosts cell survival and proliferation. PtdIns(3,4,5)P3 partly achieves these functions by triggering activation of the kinase Akt, which phosphorylates targets like Tsc2 and GSK3β. Consequently, unchecked upregulation of PtdIns(3,4,5)P3-Akt signaling promotes tumor progression. Interestingly, 50–70% of PtdIns and PtdInsPs have stearate and arachidonate at sn-1 and sn-2 positions of glycerol, respectively, forming a species known as 38:4-PtdIns/PtdInsPs. LCLAT1 and MBOAT7 acyltransferases partly enrich PtdIns in this acyl format. We previously showed that disruption of LCLAT1 lowered PtdIns(4,5)P2 levels and perturbed endocytosis and endocytic trafficking. However, the role of LCLAT1 in receptor tyrosine kinase and PtdIns(3,4,5)P3 signaling was not explored. Here, we show that LCLAT1 silencing in MDA-MB-231 and ARPE-19 cells abated the levels of PtdIns(3,4,5)P3 in response to EGF signaling. Importantly, LCLAT1-silenced cells were also impaired for EGF-driven and insulin-driven Akt activation and downstream signaling. Thus, our work provides first evidence that the LCLAT1 acyltransferase is required for receptor tyrosine kinase signaling.

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PREX2

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