ArticleProceedings of the National Academy of Sciences of the United States of America2015
Cyclin-dependent kinase 5 activates guanine nucleotide exchange factor GIV/Girdin to orchestrate migration-proliferation dichotomy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 65 citations in OpenAlex.
- The Duality of Cdk5: A Master Regulator in Neurodevelopment and a Hijacked Oncogene in Cancer.Cells · 2025Review
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- Long-Chain Cyclic Arylguanidines as Multifunctional Serotonin Receptor Ligands with Antiproliferative Activity.ACS omega · 2025Article
- CDK5: Insights into its roles in diseases.Molecular biology reports · 2025Review
- Heterotrimeric G protein signaling without GPCRs: The Gα-binding-and-activating (GBA) motif.The Journal of biological chemistry · 2024Review
- Predictive data-driven modeling of C-terminal tyrosine function in the EGFR signaling network.Life science alliance · 2023Article
- A circuit for secretion-coupled cellular autonomy in multicellular eukaryotic cells.Molecular systems biology · 2023Article
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- Post-translational modifications of CDK5 and their biological roles in cancer.Molecular biomedicine · 2021Review
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- Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development-Review.International journal of molecular sciences · 2021Review
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- Receptor tyrosine kinases activate heterotrimeric G proteins via phosphorylation within the interdomain cleft of Gαi.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells.Cancer science · 2020Article
- CDK5 Inhibition Abrogates TNBC Stem-Cell Property and Enhances Anti-PD-1 Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2020Article
- Retrospective assessment of cyclin-dependent kinase 5 mRNA and protein expression and its association with patient survival in breast cancer.Journal of cellular and molecular medicine · 2020Article
- Ric-8A, a GEF, and a Chaperone for G Protein α-Subunits: Evidence for the Two-Faced Interface.BioEssays : news and reviews in molecular, cellular and developmental biology · 2020Article
- The Gα-interacting vesicle-associated protein interacts with and promotes cell surface localization of GRP78 during endoplasmic reticulum stress.FEBS letters · 2020Article
- Phosphorylation of adducin-1 by cyclin-dependent kinase 5 is important for epidermal growth factor-induced cell migration.Scientific reports · 2019Article
- CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity.Nature communications · 2019Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Signals propagated by receptor tyrosine kinases (RTKs) can drive cell migration and proliferation, two cellular processes that do not occur simultaneously--a phenomenon called "migration-proliferation dichotomy." We previously showed that epidermal growth factor (EGF) signaling is skewed to favor migration over proliferation via noncanonical transactivation of Gαi proteins by the guanine exchange factor (GEF) GIV. However, what turns on GIV-GEF downstream of growth factor RTKs remained unknown. Here we reveal the molecular mechanism by which phosphorylation of GIV by cyclin-dependent kinase 5 (CDK5) triggers GIV's ability to bind and activate Gαi in response to growth factors and modulate downstream signals to establish a dichotomy between migration and proliferation. We show that CDK5 binds and phosphorylates GIV at Ser1674 near its GEF motif. When Ser1674 is phosphorylated, GIV activates Gαi and enhances promigratory Akt signals. Phosphorylated GIV also binds Gαs and enhances endosomal maturation, which shortens the transit time of EGFR through early endosomes, thereby limiting mitogenic MAPK signals. Consequently, this phosphoevent triggers cells to preferentially migrate during wound healing and transmigration of cancer cells. When Ser1674 cannot be phosphorylated, GIV cannot bind either Gαi or Gαs, Akt signaling is suppressed, mitogenic signals are enhanced due to delayed transit time of EGFR through early endosomes, and cells preferentially proliferate. These results illuminate how GIV-GEF is turned on upon receptor activation, adds GIV to the repertoire of CDK5 substrates, and defines a mechanism by which this unusual CDK orchestrates migration-proliferation dichotomy during cancer invasion, wound healing, and development.
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