Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, MD 21201, USA.
Mol Cancer. 2010 Sep 26;9:260. doi: 10.1186/1476-4598-9-260.
Osteopontin (OPN) has been shown to play many roles in the progression of cancer. We have recently demonstrated the activation of Akt by OPN. Integrin-linked kinase and PI3-kinase are integral proteins in OPN/AKT pathway in PC3 cells. To investigate the role of the extracellular receptors in OPN signaling, we have examined the spatio-temporal regulation of CD44 and integrin αvβ3 receptor in OPN-induced Akt activation in PC3 cells.
Here, our studies demonstrate that OPN can activate Akt either through the αVβ3 integrin or the CD44 cell surface receptor. Members of the Mitogen Activated Protein Kinase (MAPK) family have been shown to be up-regulated in a variety of human cancers and have been implicated in the metastatic behavior. Our studies have demonstrated an increase in the phosphorylation of c-Raf at Ser259 and Ser338 in PC3 cells over-expressing OPN. This increase matches up with the Erk1/2 phosphorylation at Thr202/204 and activation. However, the inhibition of Akt activity augments the phosphorylation state of ERK1/2 to two to three fold with a concomitant reduction in the phosphorylation state of c-Raf at Ser259.
Regulation c-Raf phosphorylation at Ser259 has a role in the anti-apoptotic pathways mediated by Akt or Raf/MEK/ERK proteins. OPN may have dual effects in the activation of Erk1/2. We propose this based on the observations that while OPN activates c-Raf and Erk1/2; it also acts to inhibit c-Raf and Erk1/2 activation through Akt pathway. Our observations suggest that the activation of c-Raf-ERK cascade may promote cell cycle arrest in prostate cancer cells and OPN signaling has a role in the anti-apoptotic mechanism.
骨桥蛋白 (OPN) 已被证明在癌症的进展中发挥多种作用。我们最近证明了 Akt 的 OPN 激活。整合素连接激酶和 PI3-激酶是 PC3 细胞中 OPN/AKT 通路的组成蛋白。为了研究细胞外受体在 OPN 信号转导中的作用，我们研究了 OPN 诱导的 PC3 细胞中 Akt 激活的 CD44 和整合素 αvβ3 受体的时空调节。
在这里，我们的研究表明，OPN 可以通过 αVβ3 整合素或 CD44 细胞表面受体激活 Akt。丝裂原激活蛋白激酶 (MAPK) 家族的成员已被证明在多种人类癌症中上调，并与转移行为有关。我们的研究表明，在过表达 OPN 的 PC3 细胞中，c-Raf 在 Ser259 和 Ser338 的磷酸化增加。这种增加与 Erk1/2 在 Thr202/204 的磷酸化和激活相匹配。然而，Akt 活性的抑制将 ERK1/2 的磷酸化状态增加到两到三倍，同时 Ser259 的 c-Raf 磷酸化状态降低。
c-Raf 在 Ser259 的磷酸化调节在 Akt 或 Raf/MEK/ERK 蛋白介导的抗凋亡途径中起作用。OPN 可能在 Erk1/2 的激活中具有双重作用。我们根据以下观察结果提出了这一观点：虽然 OPN 激活 c-Raf 和 Erk1/2；它还通过 Akt 途径作用于抑制 c-Raf 和 Erk1/2 的激活。我们的观察表明，c-Raf-ERK 级联的激活可能促进前列腺癌细胞的细胞周期停滞，OPN 信号在抗凋亡机制中起作用。
