Browsing Pathways

Mitogen-activated protein kinases (MAPKs) are serine/threonine kinases that mediate intracellular signaling associated with a variety of cellular activities including cell proliferation, differentiation, survival, death, and transformation [1, 2]. The three main members that integrate the MAPK family in mammalian cells are stress-activated protein kinase c-Jun NH2-terminal kinase (JNK), stress-activated protein kinase 2 (SAPK2, p38), and the extracellular signal-regulated protein kinases (ERK1/2, p44/p42). ERK has a threonine-glutamic acid-tyrosine (Thr-Glu-Tyr) motif [79, 80] that plays a central role in stimulation of cell proliferation [81, 82]. The biological consequences of phosphorylation of ERK substrates include increased proliferation, differentiation, survival [83], angiogenesis [84], motility [85], and invasiveness [86]. The ERK pathway is triggered mainly by mitogens and cytokines (Figure 1), acting through receptor tyrosine kinases, G-protein-coupled receptors, and nonnuclear activated steroid hormone receptors [4, 65]. Most of the signals activating the ERK pathway are initiated through receptor-mediated activation of Ras [4] by stimulating the exchange of GDP bound to Ras for GTP [91]. Then, Ras phosphorylates Raf-1. Then, a MAPK cascade is initiated in which Raf-1 sequentially phosphorylates MEK1/2 and ERK1/2. Later, ERK1/2 translocate to the nucleus in a process that culminates in modulation of gene transcription through the activation of several transcription factors such as Ets-1 [4], ATF-2, c-Fos, c-Myc, Elk-1 [92], or NF-κB [29] (Figure 1). At the same time, ERK1/2 can also phosphorylate cytoplasmic and nuclear kinases, such as MNK1, MNK2, MPKAP-2, RSK, or MSK1 [90]. TGF-β and EGF are growth factors that can induce tumor progression by means of the ERK pathway [93–96]. Several studies showed that these factors are overexpressed in prostate cancer in comparison with normal tissue [95–98]. In different tumor cells, expression of some EGF family members such as EGF or TGF-α is associated with poor patient prognosis or resistance to chemotherapeutics [94–99]. IGF-1 and EGF stimulate intracellular signaling pathways converging at the level of ERK2 [100], which is a key kinase mediator of growth-factor-induced mitogenesis in prostate cancer cells [101]. The two major substrates of the IGF-1 receptor, insulin receptor substrate-1 [102] and Shc, are known to contribute to IGF-1-induced activation of ERK [103]. The ERK signaling pathway plays a role in several steps of tumor development [14]. In fact, some components of the Raf-MEK-ERK pathway are activated in solid tumors (such as prostate or breast cancer) and hematological malignances [104–106]. In approximately 30% of human breast cancers, mutations are found in the ERK1/2 MAPK pathway [65]. ERK1/2 and downstream ERK1/2 targets are hyperphosphorylated in a large subset of mammary tumors [107]. Mutations of K-Ras appear frequently in many cancers including those of the lung and colon [108]. Mutations in the B-Raf gene are responsible for 66% of malignant melanomas [109]. Increased expressions of Raf pathway has been associated with advanced prostate cancer, hormonal independence, metastasis, and a poor prognosis [110]. Moreover, prostate cancer cell lines isolated from patients with advanced cancer (LNCaP, PC3, DU145) expressed low levels of active Raf kinase inhibitors [105]. TNF-α acts as an ERK activator in some cases related to inflammation and cell proliferation. In this way, Ricote et al. [11] showed that ERK phosphorylation was notably increased by TNF-α in a dose-dependent manner in LNCaP cells. In prostate cancer, presence of Raf-1 and MEK1 in conjunction with elevated ERK1 and ERK2, and their phosphorylated forms, suggests that stimulation of cell proliferation could be triggered by IL-6 via the ERK pathway [104]. In fact, IL-6 expression increased in prostate cancer in comparison with normal tissue [104, 111]. Moreover, LNCaP cells which produce IL-6 show increased proliferation, at least in part, due to ERK activation [112]. Recently, a phase I clinical trial has revealed the ability of an anti-IL-6 antibody (siltuximab) to inhibit ERK1/2 phosphorylation in prostate tumors [113].

Sonic hedgehog is a protein that in humans is encoded by the SHH ("sonic hedgehog") gene.[5] Both the gene and the protein may also be found notated alternatively as "Shh". Sonic hedgehog is one of three proteins in the mammalian signaling pathway family called hedgehog, the others being desert hedgehog (DHH) and Indian hedgehog (IHH). SHH is the best studied ligand of the hedgehog signaling pathway. It plays a key role in regulating vertebrate organogenesis, such as in the growth of digits on limbs and organization of the brain. Sonic hedgehog is the best established example of a morphogen as defined by Lewis Wolpert's French flag model—a molecule that diffuses to form a concentration gradient and has different effects on the cells of the developing embryo depending on its concentration. SHH remains important in the adult. It controls cell division of adult stem cells and has been implicated in the development of some cancers.