Growth factor regulation of estrogen receptor coregulator PELP1 functions via protein kinase A pathway

Jatin K. Nagpal, Sujit Nair, Dimple Chakravarty, Rajib Rajhans, Saikumar Pothana, Darrell W Brann, Rajeshwar Rao Tekmal, Ratna K. Vadlamudi

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

PELP1 (proline-rich, glutamic acid-rich, and leucine-rich protein-1) is a potential proto-oncogene that functions as a coregulator of estrogen receptor (ER), and its expression is deregulated during breast cancer progression. Emerging evidence suggests growth factor signaling crosstalk with ER as one possible mechanism by which breast tumors acquire resistance to therapy. In this study, we examined mechanisms by which growth factors modulate PELP1 functions, leading to activation of ER. Using in vivo labeling assays, we have found that growth factors promote phosphorylation of PELP1. Utilizing a panel of substrate-specific phosphorylated antibodies, we discovered that growth factor stimulation promotes phosphorylation of PELP1 that is recognized by a protein kinase A (PKA) substrate-specific antibody. Accordingly, growth factor-mediated PELP1 phosphorylation was effectively blocked by PKA-specific inhibitor H89. Utilizing purified PKA enzyme and in vitro kinase assays, we obtained evidence of direct PELP1 phosphorylation by PKA. Using deletion and mutational analysis, we identified PELP1 domains that are phosphorylated by PKA. Interestingly, site-directed mutagenesis of the putative PKA site in PELP1 compromised growth factor-induced activation and subnuclear localization of PELP1 and also affected PELP1-mediated transactivation function. Utilizing MCF-7 cells expressing a PELP1 mutant that cannot be phosphorylated by PKA, we provide mechanistic insights by which growth factor signaling regulates ER transactivation in a PELP1-dependent manner. Collectively, these findings suggest that growth factor signals promote phosphorylation of ER coactivator PELP1 via PKA pathway, and such modification may have functional implications in breast tumors with deregulated growth factor signaling.

Original languageEnglish (US)
Pages (from-to)851-861
Number of pages11
JournalMolecular Cancer Research
Volume6
Issue number5
DOIs
StatePublished - May 1 2008

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Cyclic AMP-Dependent Protein Kinases
Estrogen Receptors
Intercellular Signaling Peptides and Proteins
Phosphorylation
Breast Neoplasms
Transcriptional Activation
Proto-Oncogenes
Antibodies
MCF-7 Cells
Site-Directed Mutagenesis
Proline
Leucine
Glutamic Acid
Phosphotransferases
Enzymes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Growth factor regulation of estrogen receptor coregulator PELP1 functions via protein kinase A pathway. / Nagpal, Jatin K.; Nair, Sujit; Chakravarty, Dimple; Rajhans, Rajib; Pothana, Saikumar; Brann, Darrell W; Tekmal, Rajeshwar Rao; Vadlamudi, Ratna K.

In: Molecular Cancer Research, Vol. 6, No. 5, 01.05.2008, p. 851-861.

Research output: Contribution to journalArticle

Nagpal, JK, Nair, S, Chakravarty, D, Rajhans, R, Pothana, S, Brann, DW, Tekmal, RR & Vadlamudi, RK 2008, 'Growth factor regulation of estrogen receptor coregulator PELP1 functions via protein kinase A pathway', Molecular Cancer Research, vol. 6, no. 5, pp. 851-861. https://doi.org/10.1158/1541-7786.MCR-07-2030
Nagpal, Jatin K. ; Nair, Sujit ; Chakravarty, Dimple ; Rajhans, Rajib ; Pothana, Saikumar ; Brann, Darrell W ; Tekmal, Rajeshwar Rao ; Vadlamudi, Ratna K. / Growth factor regulation of estrogen receptor coregulator PELP1 functions via protein kinase A pathway. In: Molecular Cancer Research. 2008 ; Vol. 6, No. 5. pp. 851-861.
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