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THE ROUTES OF ERK ACTIVATION IN PROLACTIN‐STIMULATED BREAST CANCER CELLS
Author(s) -
Aksamitiene Edita,
Achanta Sirisha,
Kiyatkin Anatoly,
Hoek Jan B
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.946.1
Subject(s) - protein kinase b , mapk/erk pathway , cancer research , pi3k/akt/mtor pathway , grb2 , signal transduction , phosphorylation , microbiology and biotechnology , kinase , biology , proto oncogene tyrosine protein kinase src , chemistry
Understanding the interactions that occur among the distinct signal transduction pathways, triggered by activation of prolactin receptor (PRL‐R), is essential in studying pathogenesis of metastatic breast cancer. Using quantitative Multi‐strip Western blotting of immunoprecipitates or total cell lysates, we show that PRL induces tyrosine phosphorylation of adaptor proteins of IRS, Grb2 and Shc families and concurrently activates Src family kinases (SFKs), Janus kinase/signal transducer and activator of transcription (JAK/STAT), Ras/mitogen activated protein kinase (MAPK) and phosphoinositide‐3 (PI3)‐kinase/Akt signaling pathways in T47D and MCF‐7 human breast cancer cells, derived from the patients with infiltrative ductal carcinoma and expressing different amounts of PRL‐R. Employing inhibitors against JAK2, STAT5, SFKs, PI3K, PDK1, Akt, PKC, Rac, PAK and Ras, we found that (1) PI3K/Akt and MAPK pathways cross‐talk upon PRL stimulation; (2) PI3K‐mediated ERK1/2 activation via c‐Raf occurs regardless of STAT5, Akt and PKC, but depends on activities of JAK2 and SFKs; (3) activated PRL‐R largely utilizes PI3K/PDK1‐dependent Rac/PAK pathway rather than canonical Shc/Grb2/SOS/Ras route to initiate, augment and sustain MAPK signaling. These findings suggest that by interconnecting such diverse pathways PLR may enhance breast cancer cell proliferation, survival, migration and invasiveness.