PELP1: a review of PELP1 interactions, signaling, and biology

Abstract

Proline, glutamic acid, and leucine rich protein 1 (PELP1) is a large multi-domain protein that has been shown to modulate an increasing number of pathways and biological processes. The first reports describing the cloning and characterization of PELP1 showed that it was an estrogen receptor coactivator. PELP1 has now been shown to be a coregulator for a growing number of transcription factors. Furthermore, recent reports have shown that PELP1 is a member of chromatin remodeling complexes. In addition to PELP1 nuclear functions, it has been shown to have cytoplasmic signaling functions as well. In the cytoplasm PELP1 acts as a scaffold molecule and mediates rapid signaling from growth factor and hormone receptors. PELP1 signaling ultimately plays a role in cancer biology by increasing proliferation and metastasis, among other cellular processes. Here we will review (1) the cloning and characterization of PELP1 expression, (2) interacting proteins, (3) PELP1 signaling, and (4) PELP1-mediated biology.

Keywords: AIB1; AR; BCAS3; CBP; CREB binding protein; ChIP; Coactivator; E2; ER; ERRα; Estrogen signaling; Extra-nuclear signaling; FHL2; GR; HDAC; Hormone resistance; IHC; ILK1; KDM1; LIM domain; Lin-1, Isl-1, and Mec-3 domain; MNAR; Modulator of Nongenomic Activity of ER; PELP1; RXR; SH2; SH3; STAT3; TIF2; amplified in breast cancer 1; androgen receptor; breast carcinoma amplified sequence 3; c-Src homology domain 2; c-Src homology domain 3; chromatin immunoprecipitation; estradiol; estrogen receptor; estrogen-related receptor alpha; four and a half LIM domains 2; glucocorticoid receptor; histone deacetylase; immunohistochemistry; integrin-linked kinase 1; lysine-specific histone demethylase 1; proline, glutamic acid and leucine rich protein 1; retinoid X receptor; signal transducer and activator or transcription 3; transcriptional mediators/intermediary factor 2.

Figure 1

Schematic representation of PELP1 domain structure.

Figure 2

Targeting PELP1 pathways during tumorigenesis. Diagram of PELP1 signaling complexes and pathways in the cytoplasm and nucleus that could be targeted with pre-clinical and clinical drugs. At the membrane, PELP1 interacting RTKs could be targeted through blocking antibodies such as cetuzimab or kinase inhibitors such as erlotinib (both targeted to EGFR). In the cytoplasm, PELP1 interacting molecules such as Src or PI3K could be inhibited using the small molecule inhibitors dasatanib or perifosine, respectively. In the nuclear compartment, PELP1 interacts with different proteins including KDM1A and CDKs, both of which have candidate therapies available. Finally, exciting pre-clinical data suggest that targeting PELP1 protein-protein interactions may be a viable treatment option, as interfering with the LXXLL motif between PELP1 and AR successfully blocked tumor growth.