Esimerkkejä netistä Ras-superperheen merkityksestä syövän säätelyssä . Geranylgeranylaatiosta esimerkki

 https://www.researchgate.net/figure/Signaling-pathways-downstream-of-Ras-a-farnesylated-small-GTPase-Ras-directly-activates_fig1_51704480

 

Signaling pathways downstream of Ras, a farnesylated small GTPase. Ras directly activates the mitogen activated protein kinase (MAPK) cascade, through phosphorylation of Raf (or other MAPK kinase kinase, MAPKKK) which in turn phosphorylates MEK (or other MAPK kinases), which then phosphorylates MAPK. On the other hand, Ras also activates Rac GTPases, which in turn activates p21-activated kinase (PAK), an Akt interacting protein. Rac also can activate Rho GTPases, which regulates actin stress fiber and focal adhesion formation by activating Rho kinase, which in turn regulates the activity of myosin light chain which controls actin polymerization.

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... by Rho kinase, a serine-threonine kinase that induces the formation of actin stress fibers and focal adhesions by phosphorylating myosin light chain (MLC), which promotes actin-binding to myosin II [ 78]. The Rho-kinase inhibitor, Y- 27632, inhibited chemotactic migration in vitro and metastatic growth of PC3 cells in immune- compromised mice, reduced MLC phosphorylation and markedly altered cell morphology [79], indicating that invasiveness of human prostate cancer is facilitated by the Rho/Rho-kinase pathway. RhoC GTPase is also expressed and activated in PC-3 cells, whereas RhoC inhibition promotes IGF-I stimulated random motility but decreases in vitro invasion and metastases, and results in drastic morphologic changes and alterations in the expression and distribution of focal adhesion-related proteins [80]. Studies indicated that RhoC was required for directed migration and invasion, whereas Rac1 was required for tumor cells to degrade the basement membrane, allowing them to escape the blood vessel (diapedesis) [81]. RhoC was increased in highly metastatic sublines of LNCaP cells, compared to the parental line, whereas treatment with a small hairpin RNA (shRNA) specific for RhoC suppressed collagen-mediated invasion [82]. Significantly, RhoC activation was selectively blocked with antibodies to α 2 β 1 indicating that RhoC was activated downstream of integrin activation. In contrast, RhoC had no effect on cell proliferation in vitro or on tumor growth in mice [83]. Immunohistochemical analyses on tumor specimens from 63 PCa patients showed that RhoC expression had no significant correlation with Gleason grade, but had significant positive correlation with both lymph node and distant metastasis, and was inversely correlated with patient survival [83]. Ras overexpression has also been associated with increased metastasis. Early studies showed that H-ras overexpression increased the metastatic ability of AT2 cells [84], although the incidence of Ras mutations in PCa patients are rare [85]. Oncogenic Ras promoted metastasis to multiple organs, including bone and brain – however, detailed analysis indicated that activa- tion of the Raf/ERK pathway downstream of Ras stimulated metastasis to the brain, while activation of the RalGEF pathway led to bone metastases, but did not affect subcutaneous tumor growth [86]. Ras has multiple effectors – including Rac and Rho and can signal to various pathways, including proliferation (through ERK/ MAPK) and motility, and is one of the most com- mon oncogenes displaying aberrant activation in human cancers (Figure 5). It can also interact with the PI3K/Akt pathway, either by PI3K inter- action or through Rac1, which in turn activates p21-activated kinase (PAK), an Akt interacting protein (Figure 5). However, since Ras activation through mutagenesis is rare in human PCa, these proteins are likely to play a more impor- tant role in metastasis. Taken together, these studies indicate an important role for isoprenylated small GTPases in advanced PCa rather than in early stage PCa. Multiple in vitro studies have demonstrated that statins inhibit isoprenylation of small GTPases in PCa cell lines. Most of these studies utilized lovastatin, the first statin to come on the market in 1987 [87], although mevastatin had been the first statin drug to be produced [88]. In vitro studies utilized lovastatin at 50 μM, which completely inhibited the production of GGPP and FPP in PCa cells [89]. Lovastatin was shown to inhibit PCa cell growth, alone or in combination with other drugs [90]. In 1999, we first demonstrated that PCa cell growth was regulated by geranylgeranylation and not by farnesylation [16]. When treated with lovastatin, PCa cell lines derived from transgenic mice with adenocarcinoma of the prostate (TRAMP) showed inactivation of the small GTPase RhoA. The geranylgeranylated Rho family, including RhoA, Rac1, and Cdc42Hs, are involved in cell shape regulation and actin filament assembly. Inacti- vating these proteins with lovastatin caused cell rounding and actin filament disassembly. Our results showed that activation of Rho proteins was necessary for cell proliferation [16]. Exogenous addition of geranylgeraniol (GGOL), but not farnesol (FOL), rescued TRAMP cells from the anti-proliferative effects of lovastatin and also translocated RhoA from the cytosol to the membrane where RhoA was active. Active RhoA was also found to be necessary for TRAMP cell prolif- eration. Our results were upheld by a 2008 study by Hoque et al., showing that lovastatin and simvastatin decreased cell survival in three PCa cell lines (PC3, DU145, and LNCaP) by inducing apoptosis and cell growth arrest at G1 phase and by suppressing RhoA activation [17]. This study also showed that HMG-CoA induced ...

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... by Rho kinase, a serine-threonine kinase tha