Pancreatic oncogenic signaling cascades converge at Protein Kinase D1.
Pancreatic oncogenic signaling cascades converge at Protein Kinase D1.
复制标题
胰腺致癌信号级联在蛋白激酶 D1 处汇聚。
DOI：
10.1080/15384101.2015.1032646
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Storz,Peter
中科院分区：
文献类型：
--
作者：
Liou,Geou-Yarh;Leitges,Michael;Storz,Peter
Although over 95% of pancreatic ductal adenocarcinoma (PDA) harbor Kras mutations, the presence of an oncogenic allele of Kras alone is not sufficient to develop pancreatic cancer. Moreover, mutant Kras is not constitutively-active per se, 1 and requires additional stimulation to initiate a feed forward loop for enhanced pathological level of activity. 2 In addition, a cooperation of signaling pathways activated by mutant Kras with signaling pathways initiated by epidermal growth factor receptor (EGFR)-activated wildtype Kras is needed for the development of PDA. 3 Given that Kras is difficult to target, an ideal strategy would be to target an enzyme that serves as a “bottleneck,” converging both pathways. In our recent work we have shown that the serine/threonine kinase Protein Kinase D1 (PKD1) functions downstream of oncogenic Kras and activated wildtype Kras (Fig. 1) and may represent such an ideal target. 4The protein kinase D family of protein kinases actually consists of 3 isoforms PKD1, PKD2 and PKD3. In normal pancreas, only PKD3 is expressed in acinar cells, whereas PKD1 is only expressed in islets of Langerhans and pancreatic ducts. 4 This expression pattern changes when pancreatic acinar cells acquire an oncogenic Kras mutation or aberrant EGFR activation. In response to such signaling acinar cells undergo acinar-to-ductal metaplasia (ADM). During ADM cells down-regulate expression of PKD3 and upregulate expression of PKD1, whereas PKD2 expression remains unchanged. 4 In addition to increased expression, PKD1
