Carboxyl-Terminal Modulator Protein Positively Regulates Akt Phosphorylation and Acts as an Oncogenic Driver in Breast Cancer

Abstract

Akt activation has been implicated broadly in tumorigenesis, but the basis for its dysregulation in cancer cells is incompletely understood. In this study, we sought to clarify a regulatory role for the Akt-binding carboxy-terminal modulator protein (CTMP), which has been controversial. In evaluating CTMP expression in paired normaltumor specimens of 198 patients with breast cancer, we found that CTMP was upregulated in breast tumors, where it was associated with poor patient survival. Notably, CTMP expression also correlated positively with Akt phosphorylation in breast cancer clinical specimens and cell lines. Furthermore, ectopic expression of CTMP promoted cell proliferation and enhanced the tumorigenic properties of estrogen-dependent breast cancer cells. This effect was correlated with increased sensitivity to insulin-induced Akt phosphorylation, which is mediated primarily by the phosphoinositide 3-kinase-Akt pathway. In contrast, short hairpin RNA-mediated silencing of endogenous CTMP decreased the proliferation of estrogen-dependent or estrogen-independent breast cancer cells. Mechanistic investigations defined the N-terminal domain of CTMP at amino acids 1 to 64 as responsible for Akt binding. Taken together, our results firmly corroborate the concept that CTMP promotes Akt phosphorylation and functions as an oncogenic molecule in breast cancer. Cancer Res; 73(20);

Carboxyl‐Terminal Modulator Protein Ameliorates Pathological Cardiac Hypertrophy by Suppressing the Protein Kinase B Signaling Pathway

“…In contrast, CTMP had the opposite effect on neuroprotection after brain injury9, 14, 17, 42 and insulin resistance,15 via restraining AKT signaling. Notably, a few reports have suggested that CTMP directly binds to AKT through the N‐terminal domain 1 to 64 amino acids at the plasma membrane,16 enhances AKT phosphorylation,43 and functions as an oncogenic molecule in head and neck squamous cell carcinoma44 and breast cancer 16, 45. These findings challenge the association of CTMP with AKT's phosphorylation condition and functional effects.…”

“…Meanwhile, accumulating evidence suggests that CTMP plays vital roles in numerous pathological processes, such as tumor,8, 12, 13 neuroprotection,14 and metabolism 15. Initially, CTMP has been determined to exert a complex influence in multiple cancers by regulating cell survival, proliferation, and angiogenesis 12, 13, 16. Moreover, mounting studies manifest that inhibition of CTMP would be beneficial in the neuroprotection in response to brain injury, no matter whether the subjects combined with diabetes mellitus or not 9, 14, 17.…”

Chemo-spectroscopic sensor for carboxyl terminus overexpressed in carcinoma cell membrane

“…This finding comes in agreement with the literature data that mention an over-expression of carboxyl terminus on the carcinoma cell. 3 The HA component is predominantly localized near the cell membrane. At a certain focal plane in the interior of the cell, the Raman images (insets Figure 5, A and B) evidence that the AuHA sensors are localized at the edge of the cell and not in the cytosol.…”

“…The binding site of this terminus is involved in glucose transport and glycogen synthesis. [1][2][3] Its overexpression enhances the glucose transport activity, glycogen and insulin synthesis 4 and tumorgenesis processes. 3 Numerous enzymatic pathways are also initiated at the carboxyl end of the plasma proteins.…”

“…[1][2][3] Its overexpression enhances the glucose transport activity, glycogen and insulin synthesis 4 and tumorgenesis processes. 3 Numerous enzymatic pathways are also initiated at the carboxyl end of the plasma proteins. 5 Furthermore serotonin, 6 aquaporins 7 and the proteins of the signal transduction 8 anchor through the C-terminus.…”