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  • The bovine Ack is called Ack bAck and has


    The bovine Ack is called Ack2 (bAck2) and has been suggested to act as a clathrin-assembly protein regulated by the small GTPase Cdc42 [17]. bAck2 lacks some of the C-terminal parts when compared to hAck1 and mAck1. Both Ack1 and Ack2 have been demonstrated to interact with sorting nexin 9 (SNX9 or SH3PX1) [18], [19]. This interaction has been demonstrated to occur through the proline-rich domains of Ack1 and -2 and the SH3 domain of SNX9. SNX9 was interestingly demonstrated to preferentially interact with inactive Ack1 [19]. SNX9, which is an endocytic accessory protein [20], binds both AP-2 and clathrin, and additionally, SNX9 has been reported to bind to and stimulate the GTPase activity of dynamin [21], [22], [23]. In the current study, we have investigated the effect of over-expressing hAck1 on endocytosis of EGF and further on intracellular sorting of endocytosed EGFR. In SR 2211 transfected with a plasmid encoding hAck1, the expressed protein was mainly found on early endosomes and in a tubulo-reticular compartment. Immuno-electron microscopy (immuno-EM) analysis showed that the endocytosed EGF-EGFR in cells with moderate over-expression of Ack1 mainly localized to early endosomes. Furthermore, the translocation to inner membranes of MVBs was inhibited, suggesting that Ack1 has a role in lysosomal sorting of endocytosed cargo. We further investigated the role of Ack1 in endocytosis of the EGFR by siRNA-mediated knock down of Ack1 in HeLa cells. Such knock down resulted in a reduced rate of 125I-EGF internalization. We further found that knock down of Ack1 affected intracellular sorting of 125I-EGF, increasing recycling and decreasing degradation of EGF.
    Materials and methods
    Results and discussion
    Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States. Median overall survival for patients with pancreatic cancer after resection of the tumor ranges from 15 to 20 months. Pancreatic carcinomas often exhibit resistance to conventional cytotoxic agents, and few effective chemotherapeutic agents are currently available for the treatment of advanced disease. New therapeutic strategies are urgently needed to improve survival outcomes. Protein kinases have emerged as a major therapeutic target for various cancers including pancreatic cancer. Most pancreatic cancers (∼90%) express epidermal growth factor receptor (EGFR). However, the phase III trial of the EGFR inhibitor erlotinib (Tarceva) with gemcitabine reported a marginal increase in the median survival of patients: 6.4 months compared with 5.9 months for patients treated with gemcitabine alone. Therefore, inhibition of EGFR alone may not be sufficient for improving survival outcomes. Inhibition of additional tyrosine kinases and their signaling networks is also needed to overcome the compensatory pathways that confer drug resistance in pancreatic cancer. A key downstream effector of receptor tyrosine kinase (RTK) signaling is AKT/PKB kinase, which is required for the growth of normal cells and is frequently activated in many cancer types., , Because of its ability to relay pro-survival signals, AKT has emerged as a major hallmark of tumor progression., , , AKT is frequently activated in pancreatic cancer, which is highly correlated with HER-2/ overexpression. Although regulation of AKT activity by PI3K and negatively by PTEN (phosphatase and tensin homolog) is well studied, many of the pancreatic cell lines and tumors expressing activated AKT had retained wild-type PTEN., However, the precise mechanistic details of tyrosine kinase–mediated AKT activation in cancers with normal PTEN and PI3K activity is poorly understood., Recent studies have established alternative modes of AKT activation, and one such kinase is Ack1. Ack1, also known as TNK2, is an ubiquitously expressed tyrosine kinase that is rapidly activated by a number of activated RTKs including those mediated by epidermal growth factor (EGF), platelet-derived growth factor, and insulin signaling., , , Robust Ack1 activation in a variety of cancer cells by multiple RTKs has been reported; however, the role of Ack1 signaling in pancreatic cancer has not been explored. Ack1 is primarily phosphorylated at Tyr284, leading to its kinase activation., The gene is also amplified in primary lung, ovarian, and prostate tumors, which correlates with poor prognosis., Auto-activating mutations in Ack1 have been reported in lung (W75R), ovarian (R99Q, E346K), and stomach (M409I) cancers., Our earlier studies have shown that Ack1 regulates prostate cancer progression to androgen independence by regulating the androgen receptor., , We have also recently uncovered another major effector of Ack1, the oncogene AKT/PKB. Ack1-mediated phosphorylation of Tyr176 in the AKT kinase domain resulted in its activation, primarily assessed by Ser473 phosphorylation, in a PI3K/PTEN-independent manner promoting mitotic progression of the cells.