Pak1 Signaling and Targets in Breast Cancer Progression

Summary

Principal Investigator: Rakesh Kumar
Abstract: DESCRIPTION (provided by applicant): Breast cancer progression is driven by deregulated proliferation, the acquisition of inappropriate invasiveness and mitotic defects, in addition to other phenotypic changes. One molecule known to cause progression of breast cancer cells to more invasive phenotypes is p21-activated kinase 1 (Pak1), a nodular kinase activated by a variety of cell surface or intracellular signals. Despite the remarkable growth of new information on the biology of Pak1 in the last decade, we still do not know how Pak1 participates in essential, regulatory events which ensure S-phase progression and controlled mitosis and how it could significantly influence the status of polyploidy in breast cancer The purpose of this project is to clarify and define for the first time the significant role of signal-dependent stimulation of Pak1 in the G1-to-S transition and in mitotic progression, in both physiological and aberrant cell proliferation. These studies are designed to offer a molecular explanation for the well-documented effect of Pak1 dysregulation at two critical points in cell cycle progression. In addition, we will test the hypothesis that E2F1 and HSF1 transcriptional factors are determinants of Pak1 functions at the G1/S phase transition and during mitosis using functionally relevant, genetic mouse models. And finally, we will evaluate and the prognostic significance of these emerging molecules in breast cancer progression. The rationale for this proposal is drawn from a number of findings from the PI's laboratory supported by R01-CA090970-09, for which we are seeking renewal. These findings to suggest that Pak1 signaling plays an inherent role in controlling the G1-to-S phase transition and mitotic progression via E2F1 or HSF1 respectively, and that E2F1 and HSF1 might be novel determinants of Pak1 functions in breast cancer cells. Our testable hypotheses are: Deregulation of Pak1 signaling stimulates E2F1- and HSF1-dependent pathways;and consequently, deregulation of Pak1 signaling confers deregulated G1-to-S-transition and mitotic progression in breast cancer cells. To address these hypotheses, our Specific Aims are to: To address these hypotheses, our Specific Aims are to: (1) Investigate the mechanism by which Pak1 regulates the G1-to-S progression by defining the impact of Pak1-phosphorylation upon the functions of E2Fs;(2) Determine the role of HSF1 in the nuclear accumulation of activated Pak1 and in mitotic progression of breast cancer cells;and (3) To study the role of E2F1 or HSF1 as determinant of Pak1 function in the G1/S transition and mitotic progression in physiological relevant model systems. Our proposed research is significant as the knowledge gained here may reveal Pak1 signaling-dependent regulation of the E2F family and HSF1 transcriptional factors for the first time, and thus, defining novel Pak1 functions in the G1-to-S-transition and mitotic progression of breast cancer cells. Additionally, this work is innovative because we will start understanding the principles by which Pak1 regulates transcription of a subset of genes with roles in the S-phase and mitosis.
Funding Period: 2001-05-18 - 2016-01-31
more information: NIH RePORT

Top Publications

  1. ncbi CRIPak, a novel endogenous Pak1 inhibitor
    A H Talukder
    Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Oncogene 25:1311-9. 2006
  2. pmc PAK thread from amoeba to mammals
    Anupam Kumar
    Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, District of Columbia 20037, USA
    J Cell Biochem 107:579-85. 2009
  3. pmc PAK signaling in oncogenesis
    P R Molli
    Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA
    Oncogene 28:2545-55. 2009
  4. pmc Extranuclear coactivator signaling confers insensitivity to tamoxifen
    Rakesh Kumar
    Department of Biochemistry and Molecular Biology, Institute of Coregulator Biology, The George Washington University Medical Center, Washington, District of Columbia 20037, USA
    Clin Cancer Res 15:4123-30. 2009
  5. pmc Nuclear receptor coregulators in cancer biology
    BERT W O'MALLEY
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
    Cancer Res 69:8217-22. 2009
  6. pmc SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration
    Weiwen Long
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030 USA
    Mol Cell 37:321-32. 2010
  7. pmc MicroRNAs and cancer therapy: the next wave or here to stay?
    Sirigiri Divijendra Natha Reddy
    Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington DC 20037, USA
    Cancer Biol Ther 9:479-82. 2010
  8. pmc Identification of a novel estrogen receptor-alpha variant and its upstream splicing regulator
    Kazufumi Ohshiro
    Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, Washington, D C 20037, USA
    Mol Endocrinol 24:914-22. 2010
  9. pmc Arpc1b, a centrosomal protein, is both an activator and substrate of Aurora A
    Poonam R Molli
    Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC 20037, USA
    J Cell Biol 190:101-14. 2010
  10. pmc Gene profiling of MTA1 identifies novel gene targets and functions
    Krishna Sumanth Ghanta
    McCormick Genomic and Proteomic Center, The George Washington University Medical Center, Washington, D C, United States of America
    PLoS ONE 6:e17135. 2011

Research Grants

  1. Molecular Response and Imaging-based Combination Strategies for Optimal PDT
    Tayyaba Hasan; Fiscal Year: 2013
  2. The role of annexin A6 in breast cancer metastasis
    Amos Malle Sakwe; Fiscal Year: 2013
  3. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
  4. Neuronal Cell Cycle and Survival
    Nicholas E Baker; Fiscal Year: 2013

Detail Information

Publications34

  1. ncbi CRIPak, a novel endogenous Pak1 inhibitor
    A H Talukder
    Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Oncogene 25:1311-9. 2006
    ..Our findings suggest that CRIPak is a novel negative regulator of the Pak1 and has a role in the modulation of Pak1-mediated ER transactivation in breast cancer cells...
  2. pmc PAK thread from amoeba to mammals
    Anupam Kumar
    Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, District of Columbia 20037, USA
    J Cell Biochem 107:579-85. 2009
    ..In this review, we have summarized the extensive information generated in lower eukaryotes and very briefly discussed the current status of PAKs in humans...
  3. pmc PAK signaling in oncogenesis
    P R Molli
    Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA
    Oncogene 28:2545-55. 2009
    ..In this review, we have summarized the complex regulation of PAK and its downstream diverse myriads of effectors, which in turn are responsible for the biological effects of PAK family of kinases in cancer cells...
  4. pmc Extranuclear coactivator signaling confers insensitivity to tamoxifen
    Rakesh Kumar
    Department of Biochemistry and Molecular Biology, Institute of Coregulator Biology, The George Washington University Medical Center, Washington, District of Columbia 20037, USA
    Clin Cancer Res 15:4123-30. 2009
    ..It has been suggested that high levels of estrogen receptor coactivators and its mislocalization may enhance the estrogen agonist activity of tamoxifen and contribute to tamoxifen resistance...
  5. pmc Nuclear receptor coregulators in cancer biology
    BERT W O'MALLEY
    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
    Cancer Res 69:8217-22. 2009
    ..The present review contains summaries of selective coactivators and corepressors that have been demonstrated to play important roles in the malignant process and emphasizes their importance for future therapeutic interventions...
  6. pmc SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration
    Weiwen Long
    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030 USA
    Mol Cell 37:321-32. 2010
    ..Our study also reveals that a nuclear receptor coactivator can act in the periphery of a cell to directly mediate activation of an enzyme...
  7. pmc MicroRNAs and cancer therapy: the next wave or here to stay?
    Sirigiri Divijendra Natha Reddy
    Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington DC 20037, USA
    Cancer Biol Ther 9:479-82. 2010
    ..All these developments make microRNAs attractive diagnostic markers as well as therapeutic targets. Here we will briefly review the opportunities and potential limitations of using microRNAs in cancer therapeutics...
  8. pmc Identification of a novel estrogen receptor-alpha variant and its upstream splicing regulator
    Kazufumi Ohshiro
    Department of Biochemistry and Molecular Biology and Institute of Coregulator Biology, The George Washington University Medical Center, Washington, D C 20037, USA
    Mol Endocrinol 24:914-22. 2010
    ..These findings revealed a role for NPE3-3 in alternative splicing and suggest that ERalpha is a physiological target of NPE3-3, leading to a constitutive nongenomic signaling pathway in breast cancer cells...
  9. pmc Arpc1b, a centrosomal protein, is both an activator and substrate of Aurora A
    Poonam R Molli
    Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC 20037, USA
    J Cell Biol 190:101-14. 2010
    ..Together, these findings reveal a new function for Arpc1b in centrosomal homeostasis. Arpc1b is both a physiological activator and substrate of Aurora A kinase and these interactions help to maintain mitotic integrity in mammalian cells...
  10. pmc Gene profiling of MTA1 identifies novel gene targets and functions
    Krishna Sumanth Ghanta
    McCormick Genomic and Proteomic Center, The George Washington University Medical Center, Washington, D C, United States of America
    PLoS ONE 6:e17135. 2011
    ..This DNA-damage responsive function of MTA1 was reported to be a P53-dependent and independent function. Here, we investigate the influence of P53 on gene regulation function of Mta1 to identify novel gene targets and functions of Mta1...
  11. pmc Lactoferrin-endothelin-1 axis contributes to the development and invasiveness of triple-negative breast cancer phenotypes
    Ngoc Han Ha
    Department of Biochemistry and Molecular Biology and Global Cancer Genomic Consortium, The George Washington University, Washington, District of Columbia 20037, USA
    Cancer Res 71:7259-69. 2011
    ....
  12. pmc Alternate estrogen receptors promote invasion of inflammatory breast cancer cells via non-genomic signaling
    Kazufumi Ohshiro
    Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC, United States of America
    PLoS ONE 7:e30725. 2012
    ..These findings only explain the failure of traditional anti-estrogen therapies in ER-positive IBC which induces the non-genomic signaling, but also opens newer avenues for design of modified therapies targeting these estrogen receptors...
  13. pmc Molecular pathways: targeting p21-activated kinase 1 signaling in cancer--opportunities, challenges, and limitations
    Jeyanthy Eswaran
    McCormick Genomic and Proteomics Center, George Washington University, Washington, DC, USA
    Clin Cancer Res 18:3743-9. 2012
    ..Here, we summarize recent findings about the PAK1 molecular pathways in human cancer and discuss the current status of PAK1-targeted anticancer therapies...
  14. pmc p21-activated kinase-1 signaling regulates transcription of tissue factor and tissue factor pathway inhibitor
    Beatriz Sánchez-Solana
    Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA
    J Biol Chem 287:39291-302. 2012
    ..For the first time, this study implicates PAK1 in coagulation processes, through its dual transcriptional regulation of TF and its inhibitor...
  15. pmc Signaling-dependent phosphorylation of mitotic centromere-associated kinesin regulates microtubule depolymerization and its centrosomal localization
    Suresh B Pakala
    Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA
    J Biol Chem 287:40560-9. 2012
    ..Although PAK1 regulates cytoskeleton and microtubule dynamics, its role in controlling the functions of MCAK remains unknown...
  16. pmc MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response
    Da qiang Li
    Department of Biochemistry and Molecular Biology, The George Washington University, Washington, DC 20037, USA
    Cell Rep 2:1657-69. 2012
    ..These findings suggest that the PAK1-MORC2 axis is critical for orchestrating the interplay between chromatin dynamics and the maintenance of genomic integrity through sequentially integrating multiple essential enzymatic processes...
  17. pmc MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions
    Sirigiri Divijendra Natha Reddy
    Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA
    Cancer Res 68:8195-200. 2008
    ....
  18. pmc Therapeutic IMC-C225 antibody inhibits breast cancer cell invasiveness via Vav2-dependent activation of RhoA GTPase
    Poonam R Molli
    Department of Molecular and Cellular Oncology, University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Clin Cancer Res 14:6161-70. 2008
    ....
  19. ncbi PAK1 hyperactivation is sufficient for mammary gland tumor formation
    R A Wang
    Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA
    Oncogene 25:2931-6. 2006
    ..Together, these findings provide the first direct evidence that Pak1 deregulation may be sufficient for the formation of mammary gland tumors...
  20. ncbi Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) interacts with PELP1 and activates MAPK
    Suresh K Rayala
    Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA
    J Biol Chem 281:4395-403. 2006
    ..These findings highlight a novel role of HRS in up-regulating MAPK, presumably involving interaction with PELP1...
  21. ncbi P21-activated kinase 1 regulation of estrogen receptor-alpha activation involves serine 305 activation linked with serine 118 phosphorylation
    Suresh K Rayala
    Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Cancer Res 66:1694-701. 2006
    ....
  22. ncbi Metastasis tumor antigen family proteins during breast cancer progression and metastasis in a reliable mouse model for human breast cancer
    Hao Zhang
    Department of Molecular and Cellular Oncology and Veterinary Medicine, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Clin Cancer Res 12:1479-86. 2006
    ..This led us to hypothesize that each member of the MTA family possesses a unique role and interacts with different pathways in the stepwise process of breast cancer development and progression...
  23. ncbi Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients
    Caroline Holm
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmo, Sweden
    J Natl Cancer Inst 98:671-80. 2006
    ..Here we studied associations between Pak1 expression and subcellular localization in tumor cells and tamoxifen resistance...
  24. ncbi Nuclear p21-activated kinase 1 in breast cancer packs off tamoxifen sensitivity
    Suresh K Rayala
    Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Texas 77030, USA
    Cancer Res 66:5985-8. 2006
    ..These findings prompt further investigation of how nuclear signaling by PAK1 may affect estrogen's action and whether tamoxifen resistance might be prevented or reversed by PAK1 inhibition...
  25. pmc Signaling-dependent and coordinated regulation of transcription, splicing, and translation resides in a single coregulator, PCBP1
    Qingchang Meng
    Molecular and Cellular Oncology, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 104:5866-71. 2007
    ..These findings establish the principle that a single coregulator can function as a signal-dependent and coordinated regulator of transcription, splicing, and translation...
  26. pmc Phosphorylation-dependent regulation of nuclear localization and functions of integrin-linked kinase
    Filippo Acconcia
    Department of Molecular and Cellular Oncology, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 104:6782-7. 2007
    ..Together, these results suggest that ILK is a PAK1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin...
  27. ncbi Phosphorylation-dependent regulation of stability and transforming potential of ETS transcriptional factor ESE-1 by p21-activated kinase 1
    Bramanandam Manavathi
    Department of Molecular and Cellular Oncology, University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    J Biol Chem 282:19820-30. 2007
    ..These findings provide novel insights into the mechanism of transformation potential of ESE-1 and discovered that ESE-1 functions are coordinately regulated by Pak1 phosphorylation and beta-TrCP-dependent ubiquitin-proteasome pathways...
  28. ncbi Estrogen induces expression of BCAS3, a novel estrogen receptor-alpha coactivator, through proline-, glutamic acid-, and leucine-rich protein-1 (PELP1)
    Anupama E Gururaj
    Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Mol Endocrinol 21:1847-60. 2007
    ..In brief, these results highlight a mechanism whereby ERalpha activation triggers a positive feedback loop leading to signal amplification in the cell...
  29. ncbi Sliding p21-activated kinase 1 to nucleus impacts tamoxifen sensitivity
    Suresh K Rayala
    Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Biomed Pharmacother 61:408-11. 2007
    ....
  30. ncbi Delivery of cytoplasmic proteins to autophagosomes
    Kazufumi Ohshiro
    Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
    Autophagy 4:104-6. 2008
    ....
  31. pmc Dynamic interplay between nitration and phosphorylation of tubulin cofactor B in the control of microtubule dynamics
    Suresh K Rayala
    Department of Molecular and Cellular Oncology, University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 104:19470-5. 2007
    ....
  32. ncbi Serine 88 phosphorylation of the 8-kDa dynein light chain 1 is a molecular switch for its dimerization status and functions
    Chunying Song
    Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    J Biol Chem 283:4004-13. 2008
    ....
  33. pmc Serine 28 phosphorylation of NRIF3 confers its co-activator function for estrogen receptor-alpha transactivation
    A H Talukder
    Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Oncogene 27:5233-42. 2008
    ....
  34. pmc Identification of novel gene targets and functions of p21-activated kinase 1 during DNA damage by gene expression profiling
    Mona Motwani
    McCormick Genomic and Proteomics Center, The George Washington University, Washington, District of Columbia, USA
    PLoS ONE 8:e66585. 2013
    ..In brief, this study identifies novel PAK1 dependent IR responsive genes which reveal new aspects of PAK1 biology. ..

Research Grants30

  1. Molecular Response and Imaging-based Combination Strategies for Optimal PDT
    Tayyaba Hasan; Fiscal Year: 2013
    ..NMSC on the other hand has many options but the high incidence puts a heavy burden on society in terms of cost and suffering. ..
  2. The role of annexin A6 in breast cancer metastasis
    Amos Malle Sakwe; Fiscal Year: 2013
    ....
  3. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  4. Neuronal Cell Cycle and Survival
    Nicholas E Baker; Fiscal Year: 2013
    ....