Correlation between PDZK1, Cdc37, Akt and Breast Cancer Malignancy: The Role of PDZK1 in Cell Growth through Akt Stabilization by Increasing and Interacting with Cdc37

Abstract

PDZ domain containing 1 (PDZK1) is a scaffold protein that plays a role in the fate of several proteins. Estrogen can induce PDZK1 gene expression; however, our recent report showed that PDZK1 expression in the breast cancer cell line MCF-7 is indirect and involves insulin-like growth factor (IGF)-1 receptor function. Such a relationship was established in cell culture systems and human breast cancer tissues. Here we show that overexpression of PDZK1 promoted an increase in cyclin D1 and enhanced anchorageindependent growth of MCF-7 cells in the absence of 17β-estradiol, suggesting that PDZK1 harbors oncogenic activity. Indeed, PDKZ1 overexpression enhanced epidermal growth factor receptor (EGFR)-stimulated MEK/ERK1/2 signaling and IGF-induced Akt phosphorylation. PDZK1 appeared to play this role, in part, by stabilizing the integrity of the growth promoting factors Akt, human epidermal growth factor receptor 2 (Her2/Neu) and EGFR. Increased Akt levels occurred via a decrease in the ubiquitination of the kinase. PDZK1 overexpression was associated with resistance to paclitaxel/5-fluorouracil/etoposide only at low concentrations. Although the increased stability of Akt was sensitive to heat shock protein 90 (HSP90) inhibition, increased levels of the cochaperone cell division cycle 37 (Cdc37), as well as its ability to bind PDZK1, appear to play a larger role in kinase stability. Using human tissue microarrays, we show strong positive correlation between PDZK1, Akt and Cdc37 protein levels, and all correlated with human breast malignancy. There were no positive correlations between PDZK1 and Cdc37 at the mRNA levels, confirming our in vitro studies. These results demonstrate a relationship between PDZK1, Akt and Cdc37, and potentially Her2/Neu and EGFR, in breast cancer, representing a new axis that can be targeted therapeutically to reduce the burden of human breast cancer.

Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis

“…We recently showed in two detailed studies that E 2 -mediated cell growth can be governed by PDZK1 [ 4 ]. We thus speculated that PARP-1 may be involved in ER-mediated growth of MCF-7 cells potentially through a control of PDZK1 expression.…”

“…We also reported that PDZK1 gene expression is not a direct product of ER stimulation; rather, it requires the expression and function of IGF-1 receptor (IGF-1R) [ 3 ]. PDZK1 appears to harbor oncogenic activity and promote cell growth by enhancing EGFR-stimulated MEK/ERK1/2 signaling and IGF-induced Akt phosphorylation [ 4 ]. Interestingly, PDZK1 plays this important role through stabilization of the integrity of Akt, Her2/Neu, and EGFR [ 4 ].…”

“…PDZK1 appears to harbor oncogenic activity and promote cell growth by enhancing EGFR-stimulated MEK/ERK1/2 signaling and IGF-induced Akt phosphorylation [ 4 ]. Interestingly, PDZK1 plays this important role through stabilization of the integrity of Akt, Her2/Neu, and EGFR [ 4 ]. The co-chaperone Cdc37 appears to play an important role in PDZK1-mediated stability of Akt [ 4 ].…”

“…Interestingly, PDZK1 plays this important role through stabilization of the integrity of Akt, Her2/Neu, and EGFR [ 4 ]. The co-chaperone Cdc37 appears to play an important role in PDZK1-mediated stability of Akt [ 4 ]. These aforementioned findings demonstrated a novel relationship between PDZK1, Akt, Her2/Neu, EGFR and Cdc37 in breast cancer unraveling a new axis that can be targeted therapeutically to reduce the burden of human breast cancer.…”

MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2

“…31 PDZK1 was also shown to interact with several signaling systems. 31,32 Recently, a crystal structure of a protein complex revealed the molecular details of a three-partner interaction involving the fourth PDZ domain of PDZK1, an A-kinase anchoring protein (D-AKAP2), and its attached PKA. 33 MAP17, through its interaction with PDZK1, has also been shown to play a role in trafficking plasma membrane proteins 18,19 ; hepatic overexpression of MAP17 in mice caused removal of PDZK1 from the plasma membrane along with the attached high-density lipoprotein receptor SR-B1, leading to increased plasma HDL levels.…”