Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes cancerous phenotypes.
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.
Vadlamudi
Ratna K
RK
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Bagheri-Yarmand
Rozita
R
Yang
Zhibo
Z
Balasenthil
Seetharaman
S
Nguyen
Diep
D
Sahin
Aysegul A
AA
den Hollander
Petra
P
Kumar
Rakesh
R
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
D002352:Carrier Proteins; D029721:Drosophila Proteins; D012694:Serine; D005982:Glutathione Transferase; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D004398:Dyneins; D000409:Alanine