Weiwen Long, Ph.D.
Department of Molecular and Cellular Biology
Ph.D.: Tulane University, New Orleans
Postdoctoral training: Baylor College of Medicine, Houston
The Interplay between Steroid Receptor Coactivators and Protein Kinases in Cancer
My research interests and expertise have been directed to the fields of growth factor signaling, steroid receptor/coactivator signaling, and the interplay between these two signaling pathways in cancer progression and metastasis. Our current research interests/projects include:
1. Role of SRC-3∆4 in anti-hormone resistant breast and prostate cancer progression and metastasis. Cross-talk between protein kinase signaling and hormone receptor signaling (including genomic and non-genomic actions) confers anti-hormone resistance and tumor invasiveness in breast and prostate cancers. Interestingly, we have found that SRC-3∆4, a splice isoform of oncogenic steroid receptor coactivator 3 (SRC-3), not only acts as a signaling adaptor to meditate EGF signal transduction, but forms a complex with ERα (or androgen receptor), PI3K, and c-Src kinase in response to E2 (or androgen) stimulation. These findings suggest that SRC-3∆4 may mediate the cross-talk between growth factor signaling and steroid receptor signaling to promote anti-hormone resistance and tumor invasiveness in breast and/or prostate cancer. To test this possibility, two major projects are being pursued. The first is to define the role of SRC-3Δ4 in castration-resistant prostate cancer progression and to identify the underlying mechanisms of how SRC-3Δ4 co-activates AR in an androgen-independent manner. The second project is to investigate whether SRC-3∆4 integrates E2 non-genomic and genomic actions to promote breast cancer progression and elicit anti-estrogen resistance.
2. ERK3 signaling in cancer progression and metastasis. Extracellular signal-regulated kinase 3 (ERK3) is a member of the atypical MAP kinase subfamily. Unlike ERK1 and ERK2 that have been studied extensively, little is known about the upstream stimuli and activators of ERK3 or its downstream targets. The function of ERK3 in cancer development and progression is virtually unknown. We recently identified a novel function of ERK3 in promoting cancer cell invasiveness by phosphorylating SRC-3 and regulating its proinvasive activity. We will continue to identify the upstream activators, regulators, and the downstream effectors (targets) of ERK3 signaling by IP-MS analyses and the subsequent functional studies. In addition, we are generating and will utilize these in vivo animal models (conditional ERK3 knock-in and/or knock-out) to elucidate the roles of ERK3 signaling in caner progression and metastasis.
Baylor College of Medicine
One Baylor Plaza,
Houston, TX 77030
Long W, Foulds C, Qin J, Ding C, Lonard DM, Tsai S, Tsai M-J, O’Malley BW. Regulation of SRC-3 proinvasive activity by ERK3-mediated phosphorylation in lung cancer cells (Molecular Cell, in review).
Hartig SM, He B, Long W, Buehrer BM, Mancini MA. (2011). Homeostatic levels of SRC-2 and SRC-3 promote early human adipogenesis. Journal of Cell Biology, 192(1):55-67. PMID: 21220509.
Long W, Yi P, Amazit L, LaMarca HL, Ashcroft F, Kumar R, Mancini MA, Tsai SY, Tsai MJ, O'Malley BW. (2010). SRC-3∆4 mediates the interaction of EGFR with FAK to promote cell migration. Molecular Cell, 37(3):321-32. PMID: 20159552.
Long W, O’Malley BW. (2010). Cross-talk among nuclear receptor coactivators and a membrane receptor promotes tumor cell growth and migration. Cell Cycle, 9(12):2269-2270. PMID: 20519947.
Foulds CE, Tsimelzon A, Long W, Le A, Tsai SY, Tsai MJ, O'Malley BW. (2010). Expression profiling reveals unexpected targets and functions of the human steroid receptor RNA activator (SRA) gene. Molecular Endocrinology, 24:1090-105. PMID: 20219889.
Li X, Amazit L, Long W, Lonard DM, Monaco JJ, O'Malley BW. (2007). Ubiquitin- and ATP-Independent Proteolytic Turnover of p21 by the REGγ-Proteasome Pathway. Molecular Cell, 26:831-842. PMID: 17588518.
Naresh A*, Long W*, Vidal GA*, Wimley WC, Marrero L, Sartor CI, Tovey S, Cooke TG, Bartlett JM, Jones FE. (2006). The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells. Cancer Research, 66(12):6412-20. (*: co-first author). PMID: 16778220.
Long W, Wagner KU, Lloyd KC, Binart N, Shillingford JM, Hennighausen L, Jones FE. (2003). Impaired differentiation and lactational failure of ERBB4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5. Development, 130(21):5257-68. PMID: 12954715.
Clark DE, Williams CC, Duplessis TT, Moring KL, Notwick AR, Long W, Lane WS, Beuvink I, Hynes NE, Jones FE. (2005). ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events. Journal of Biological Chemistry, 280(25):24175-80. PMID: 15863494.
Li L, Cleary S, Long W, Mandarano MA, Birchmeier C, and Jones EF. (2002). The breast proto-oncogene, HRG alpha regulates epithelial proliferation and lobuloalveolar functional development in the mouse mammary gland. Oncogene, 21:4900-4907. PMID: 12118369.