ArticlePloS one2011
p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 47 citations in OpenAlex.
- Gravitational and mechanical forces shape mitochondrial translation.Nature communications · 2026Article
- Modulating PAK1: Accessory Proteins as Promising Therapeutic Targets.Biomolecules · 2025Review
- Versatility of 14-3-3 proteins and their roles in bone and joint-related diseases.Bone research · 2024Review
- Kinase signalling adaptation supports dysfunctional mitochondria in disease.Frontiers in molecular biosciences · 2024Review
- p21-activated kinase 1 (PAK1) as a therapeutic target for cardiotoxicity.Archives of toxicology · 2022Review
- Rho family GTPase signaling through type II p21-activated kinases.Cellular and molecular life sciences : CMLS · 2022Review
- Review
- The role of 14-3-3 proteins in cell signalling pathways and virus infection.Journal of cellular and molecular medicine · 2021Review
- PAK1 Silencing Attenuated Proinflammatory Macrophage Activation and Foam Cell Formation by Increasing PPAROxidative medicine and cellular longevity · 2021Article
- CDK4/6 inhibition synergizes with inhibition of P21-Activated Kinases (PAKs) in lung cancer cell lines.PloS one · 2021Article
- Identification of a novel PAK1 inhibitor to treat pancreatic cancer.Acta pharmaceutica Sinica. B · 2020Article
- P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer.Theranostics · 2020Review
- Discovery of a small-molecule inhibitor of specific serine residue BAD phosphorylation.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Regulation of neuronal survival by DNA methyltransferases.Neural regeneration research · 2017Review
- Subverting Host Cell P21-Activated Kinase: A Case of Convergent Evolution across Pathogens.Pathogens (Basel, Switzerland) · 2017Review
- Anti-cancer effect of novel PAK1 inhibitor via induction of PUMA-mediated cell death and p21-mediated cell cycle arrest.Oncotarget · 2017Article
- Deciphering the link between PI3K and PAK: An opportunity to target key pathways in pancreatic cancer?Oncotarget · 2017Review
- Sigma-1 receptor directly interacts with Rac1-GTPase in the brain mitochondria.BMC biochemistry · 2015Article
- Clinicopathological and cellular signature of PAK1 in human bladder cancer.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Article
- Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
backgroundCell survival depends on the balance between protective and apoptotic signals. When the balance of signals tips towards apoptosis, cells undergo programmed cell death. This balance has profound implications in diseases including cancer. Oncogenes and tumor suppressors are mutated to promote cell survival during tumor development, and many chemotherapeutic drugs kill tumor cells by stimulating apoptosis. BAD is a pro-apoptotic member of the Bcl-2 family of proteins, which can be phosphorylated on numerous sites to modulate binding to Bcl-2 and 14-3-3 proteins and inhibit its pro-apoptotic activities. One of the critical phosphorylation sites is the serine 112 (S112), which can be phosphorylated by several kinases including Pak1. METHODOLOGY/PRINCIPAL
findingsWe mapped the Pak phosphorylation sites by making serine to alanine mutations in BAD and testing them as substrates in in vitro kinase assays. We found that the primary phosphorylation site is not S112 but serine 111 (S111), a site that is sometimes found phosphorylated in vivo. In transfection assays of HEK293T cells, we showed that Pak1 required Raf-1 to stimulate phosphorylation on S112. Mutating either S111 or S112 to alanine enhanced binding to Bcl-2, but the double mutant S111/112A bound better to Bcl-2. Moreover, BAD phosphorylation at S111 was observed in several other cell lines, and treating one of them with the Pak1 inhibitor 2,2'-Dihydroxy-1,1'-dinaphthyldisulfide (IPA-3) reduced phosphorylation primarily at S112 and to a smaller extent at S111, while Raf inhibitors only reduced phosphorylation at S112. CONCLUSION/SIGNIFICANCE: Together, these findings demonstrate that Pak1 phosphorylates BAD directly at S111, but phosphorylated S112 through Raf-1. These two sites of BAD serve as redundant regulatory sites for Bcl-2 binding.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.