PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

Barrows, Douglas; He, John Z.; Parsons, Ramon

doi:10.1074/jbc.m116.723882

Cited by 22 publications

(15 citation statements)

References 49 publications

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“…P-Rex activity is also regulated by a negative phosphorylation of the DEP domain by protein kinase A (PKA), which results in an autoinhibitory interaction with the DH/PH domains (Kazanietz et al, 2018). PAK has also been shown to phosphorylate P-Rex1 and P-Rex2, decreasing its GEF activity in a feedback inhibition manner (Barrows et al, 2015;Barrows et al, 2016). Thus, phosphorylation patterns in both P-Rex1 and 2 regulate Rac1 activation and has potential for designing novel targeted therapies (Mayeenuddin and Garrison, 2006;Montero et al, 2016).…”

Section: Targeting Vav1/2/3mentioning

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 Vav1/2/3mentioning

confidence: 99%

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maldonado

Medina

Velázquez

et al. 2020

Front. Cell Dev. Biol.

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“…Variants of the PREX1 gene on chromosome 20q12-13.1were associated with increased risk of diabetes mellitus type 2 and increased BMI in a cohort of European Americans 65 , through mechanisms are yet insufficiently understood 66 . Variants of the KCNB1 gene in humans are associated with increases of waist to hip ratio, fasting insulin, and triglycerides, as well as decreased insulin sensitivity 67,68 .…”

Section: Discussionmentioning

confidence: 99%

Polygenic scores for major depressive disorder and depressive symptoms predict response to lithium in patients with bipolar disorder

Amare

Schubert

Hou

et al. 2018

Preprint

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Background: Lithium is a first-line medication for bipolar disorder (BD), but only ~30% of patients respond optimally to the drug. Since genetic factors are known to mediate lithium treatment response, we hypothesized whether polygenic susceptibility to the spectrum of depression traits is associated with treatment outcomes in patients with BD. In addition, we explored the potential molecular underpinnings of this relationship. Methods:Weighted polygenic scores (PGSs) were computed for major depressive disorder (MDD) and depressive symptoms (DS) in BD patients from the Consortium on Lithium Genetics (ConLi + Gen; n=2,586) who received lithium treatment. Lithium treatment outcome was assessed using the ALDA scale. Summary statistics from genome-wide association studies (GWAS) in MDD (130,664 cases and 330,470 controls) and DS (n=161,460) were used for PGS weighting. Associations between PGSs of depression traits and lithium treatment response were assessed by binary logistic regression. We also performed a crosstrait meta-GWAS, followed by Ingenuity® Pathway Analysis.Outcomes: BD patients with a low polygenic load for depressive traits were more likely to respond well to lithium, compared to patients with high polygenic load (MDD: OR =1.64 [95%CI: 1.26-2.15], lowest vs highest PGS quartiles; DS: OR=1.53 [95%CI: 1.18-2.00]).Associations were significant for type 1, but not type 2 BD. Cross-trait GWAS and functional characterization implicated voltage-gated potassium channels, insulin-related pathways, mitogen-activated protein-kinase (MAPK) signaling, and miRNA expression.Interpretation: Genetic loading to depression traits in BD patients lower their odds of responding optimally to lithium. Our findings support the emerging concept of a lithiumresponsive biotype in BD. Funding: see attached detailsKeywords: lithium treatment, Major depressive disorder, depressive symptoms, depressive traits, bipolar disorder, polygenic score, pharmacogenomics, Voltage-gated potassium channel, insulin, MAPK. Word countAbstract: 243 main text: 3199 0

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“…P-Rex1 is also regulated by phosphorylations by protein kinase C (PKC), protein kinase A (PKA), and Pak, which in all cases negatively regulate its activation. P-Rex1 and protein kinase A (PKA) are reciprocally regulated, since P-Rex1 contributes to the spatiotemporal localization of this kinase, hence highlighting potential scaffolding functions of this GEF (54–57). …”

Section: Aberrant Rac Inputs and Outputs In Human Cancermentioning

confidence: 99%

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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PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

Cited by 22 publications

References 49 publications

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Polygenic scores for major depressive disorder and depressive symptoms predict response to lithium in patients with bipolar disorder

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

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