title: Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes cancerous phenotypes.
abstract: We identified dynein light chain 1 (DLC1) as a physiologic substrate of p21-activated kinase 1 (Pak1). Pak1-DLC1 interaction plays an essential role in cell survival, which depends on Pak1's phosphorylation of DLC1 on Ser88. Pak1 associates with the complex of DLC1 and BimL, a proapoptotic BH3-only protein, and phosphorylates both proteins. Phosphorylation of BimL by Pak1 prevents it from interacting with and inactivation of Bcl-2, an antiapoptotic protein. Overexpression of DLC1 but not DLC1-Ser88Ala mutant promotes cancerous properties of breast cancer cells. DLC1 protein level is elevated in more than 90% of human breast tumors. The regulation of cell survival functions by Pak1-DLC1 interaction represents a novel mechanism by which a signaling kinase might regulate the cancerous phenotypes.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
authors.forename: Rozita
authors.initials: R
authors.lastname: Bagheri-Yarmand
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Yang
authors.forename: Seetharaman
authors.initials: S
authors.lastname: Balasenthil
authors.forename: Diep
authors.initials: D
authors.lastname: Nguyen
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.forename: Petra
authors.initials: P
authors.lastname: den Hollander
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000409:Alanine / Q000737:chemistry; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology; D002352:Carrier Proteins / Q000494:pharmacology*; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D029721:Drosophila Proteins; D004398:Dyneins; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D009154:Mutation; D009369:Neoplasms / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation; D054462:p21-Activated Kinases
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; D012694:Serine; D005982:Glutathione Transferase; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D004398:Dyneins; D000409:Alanine