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.

CrkL meditates CCL20/CCR6-induced EMT in gastric cancer

“…As reported, the abnormal activation of CrkL-Erk1/2 pathway in human sacral chondrosarcoma mediated cell proliferation and EMT progression [24]. Together with our results, CrkL-Erk1/2 pathway can be recommended as a useful target to antagonize EMT [25,26]. For another thing, the effects of PI3 K/Akt pathway on EMT of tumors have been reported extensively [27,28].…”

C23 protein meditates bone morphogenetic protein-2-mediated EMT via up-regulation of Erk1/2 and Akt in gastric cancer

“…Erk1/2 pathway can be activated by various factors, such as chemokines and inflammation mediators. More and more studies found that the dysfunction of Erk1/2 signaling is the most common cause of cancer-initiating progression, which greatly promotes malignancy phenotype of tumors [20]. Targeting these kinases offers promise of novel therapies [21].…”

Prohibitin 1 Regulates the H19-Igf2 Axis and Proliferation in Hepatocytes

“…Despite this strong evidence of anti-tumorigenic properties of PHB1, a number of studies have indicated the pro-tumorigenic effects of PHB1. Membrane-associated PHB1 interacts with C-Raf and is indispensable for the activation of the RasRaf-MEK-ERK signaling pathway, which may modulate cancer cell survival and migration (10). Also, Phb1 is up-regulated in many cancers such as breast, prostate, ovarian, lung, bladder, thyroid, and gastric cancer (9).…”

“…However, a direct effect of c-Myc on Phb1 transcription has not been reported so far. It is possible that the controversial role of Phb1 in tumorigenesis and cell survival may be explained by cell type-specific mechanisms, subcellular localization, and even protein post-translational modifications such as phosphorylation (10).…”