ArticleMolecular and cellular biology1999
Signals from the Ras, Rac, and Rho GTPases converge on the Pak protein kinase in Rat-1 fibroblasts.
Article in Molecular and cellular biology, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 141 citations in OpenAlex.
- Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer.International journal of molecular sciences · 2025Article
- Inhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma.Biomolecules · 2025Article
- Review
- Fluorescent Chiral Quantum Dots to Unveil Origin-Dependent Exosome Uptake and Cargo Release.ACS applied bio materials · 2024Article
- Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies.Signal transduction and targeted therapy · 2023Review
- PAK1 and Therapy Resistance in Melanoma.Cells · 2023Review
- A chemorepellent inhibits local Ras activation to inhibit pseudopod formation to bias cell movement away from the chemorepellent.Molecular biology of the cell · 2022Article
- Crystal structure of a guanine nucleotide exchange factor encoded by the scrub typhus pathogenProceedings of the National Academy of Sciences of the United States of America · 2020Article
- An endogenous chemorepellent directs cell movement by inhibiting pseudopods at one side of cells.Molecular biology of the cell · 2019Article
- The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic.Biochemical Society transactions · 2018Review
- Induction of non-apoptotic programmed cell death by oncogenic RAS in human epithelial cells and its suppression by MYC overexpression.Carcinogenesis · 2018Article
- P21-activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells.Molecular carcinogenesis · 2017Article
- The role of 8-oxoguanine DNA glycosylase-1 in inflammation.International journal of molecular sciences · 2014Review
- Molecular pathways: targeting RAC-p21-activated serine-threonine kinase signaling in RAS-driven cancers.Clinical cancer research : an official journal of the American Association for Cancer Research · 2014Review
- Activation of P21-activated protein kinase 2 is an independent prognostic predictor for patients with gastric cancer.Diagnostic pathology · 2014Article
- Rho GTPases modulate malignant transformation of tumor cells.Small GTPases · 2014Review
- Novel role for p21-activated kinase 2 in thrombin-induced monocyte migration.The Journal of biological chemistry · 2013Article
- PAK signaling in cancer.Cellular logistics · 2012Article
- p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112.PloS one · 2011Article
- Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Ras plays a key role in regulating cellular proliferation, differentiation, and transformation. Raf is the major effector of Ras in the Ras > Raf > Mek > extracellular signal-activated kinase (ERK) cascade. A second effector is phosphoinositide 3-OH kinase (PI 3-kinase), which, in turn, activates the small G protein Rac. Rac also has multiple effectors, one of which is the serine threonine kinase Pak (p65(Pak)). Here we show that Ras, but not Raf, activates Pak1 in cotransfection assays of Rat-1 cells but not NIH 3T3 cells. We tested agents that activate or block specific components downstream of Ras and demonstrate a Ras > PI 3-kinase > Rac/Cdc42 > Pak signal. Although these studies suggest that the signal from Ras through PI 3-kinase is sufficient to activate Pak, additional studies suggested that other effectors contribute to Pak activation. RasV12S35 and RasV12G37, two effector mutant proteins which fail to activate PI 3-kinase, did not activate Pak when tested alone but activated Pak when they were cotransfected. Similarly, RacV12H40, an effector mutant that does not bind Pak, and Rho both cooperated with Raf to activate Pak. A dominant negative Rho mutant also inhibited Ras activation of Pak. All combinations of Rac/Raf and Ras/Raf and Rho/Raf effector mutants that transform cells cooperatively stimulated ERK. Cooperation was Pak dependent, since all combinations were inhibited by kinase-deficient Pak mutants in both transformation assays and ERK activation assays. These data suggest that other Ras effectors can collaborate with PI 3-kinase and with each other to activate Pak. Furthermore, the strong correlation between Pak activation and cooperative transformation suggests that Pak activation is necessary, although not sufficient, for cooperative transformation of Rat-1 fibroblasts by Ras, Rac, and Rho.
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