Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway

Abstract

Prohibitins are members of a highly conserved protein family containing the stomatin/prohibitin/flotillin/HflK/C (SPFH) domain (also known as the prohibitin [PHB] domain) found in unicellular eukaryotes, fungi, plants, animals, and humans. Two highly homologous members of prohibitins expressed in eukaryotes are prohibitin (PHB; B-cell receptor associated protein-32, BAP-32) and prohibitin 2/repressor of estrogen receptor activity (PHB2, REA, BAP-37). Both PHB and REA/PHB2 are ubiquitously expressed and are present in multiple cellular compartments including the mitochondria, nucleus, and the plasma membrane. Multiple functions have been attributed to the mitochondrial and nuclear PHB and PHB2/REA including cellular differentiation, anti-proliferation, and morphogenesis. One of the major functions of the prohibitins are in maintaining the functional integrity of the mitochondria and protecting cells from various stresses. In the present review, we focus on the recent research developments indicating that PHB and PHB2/REA are involved in maintaining cellular survival through the Ras-Raf-MEK-Erk pathway. Understanding the molecular mechanisms by which the intracellular signaling pathways utilize prohibitins in governing cellular survival is likely to result in development of therapeutic strategies to overcome various human pathological disorders such as diabetes, obesity, neurological diseases, inflammatory bowel disease, and cancer.

Fig. 1

Schematic domain representation of human prohibitin 1 (hPHB1) and human repressor of estrogen activity (REA/hPHB2) proteins. N, amino terminal; C, carboxylic terminal.

Fig. 2

A schematic model showing the protective mechanisms of PHB/PHB1 against staurosporine (STS)-induced apoptosis in granulosa cells (GCs). STS induces up-regulation of Bax and Bak with inhibition of Bcl2 and Bcl-xl, leading to alteration in the permeability of mitochondria as reflected by release of mitochondrial cytochrome c, which causes activation of caspase-3, and eventually execution of the apoptotic program. PHB/PHB1 blocks up-regulation of Bax and Bak through up-regulation of pErK, Bcl2 and Bclxl, and consequently suppresses downstream apoptotic events by preventing the release of mitochondrial cytochrome c and activation of caspases-3.