The HH signaling has also

The HH signaling has also been implicated in the regulation of cancer stem γ-Linolenic Acid methyl ester (CSC) by promoting their self-renewal [53]. Activated HH signaling has been identified in CSCs of many solid tumors, such as glioblastoma, breast, colon, pancreatic cancer, melanoma, and hematological malignancies, including CML and multiple myeloma, and has been shown to increase tumor-initiating populations and contribute to self-renewal, growth and tumorigenicity. Similarly, these CSC-promoting effects can be abrogated by inhibiting SMO. Evidence of crosstalk between HH-GLI and other oncogenic signaling pathways, such as PI3K/AKT/mTOR, Notch, TGFβ, Wnt/βcatenin, has been reported in many types of cancer and extensively described by recent reviews [54], [55], [56], [57], [58]. Here we will focus on the interaction between HH-GLI and the final MAPK effectors ERK1/2, p38 and JNK in cancer cells. However, we also discuss findings obtained in normal cells where possible mechanisms of interaction relevant for cancer cells have been described. Non-canonical HH signaling activation involving MAPK has also been described in normal cells and tissues. For instance, specification of oligodendrocyte progenitors by SHH is blocked by the SMO antagonist cyclopamine and PD173074, an inhibitor of FGFR [59]. During limb development induction of SHH by FGF is mediated by the ERK1/2 [60]. MAPK has been shown to modulate the expression of IHH in chondrocytic cells. MEK1/2 inhibitor UO126 decreases levels of IHH mRNA. Conversely, constitutively active MEK1 or MKK3 increase IHH levels, which are diminished by dominant-negative MEK1 [61]. To date, there is no evidence of crosstalk between HH-GLI pathway and non classical MAPK neither in normal nor in cancer cells.
Crosstalk between HH-GLI and ERK1/2 signaling The first direct evidence of a crosstalk between HH and ERK1/2 signaling came from a study performed in normal NIH/3T3 cells. This report showed that activated MEK1 (S218E, S222E or Δ32-51) stimulates expression and transcriptional activity of GLI proteins, with consequent induction PTCH1 and GLI1 target genes, showing for the first time that ERK1/2 act upstream of HH-GLI signaling. Consistently, co-expression of activated MEK1 and GLI1 or GLI2 induces a synergistic increase in GLI transcriptional activity, that is blocked by the MEK1/2 inhibitor PD98059 [62]. Interestingly, this study identified for the first time the N-terminus of GLI1 (amino acids 1-130) as a critical region for sensing the ERK1/2 pathway. Indeed, deletion of this region produces active GLI1 protein with greatly reduced response to activation by MEK1. Nevertheless, in vitro kinase assays showed that GLI1 is not directly phosphorylated by ERK1/2, suggesting that the N-terminal region of GLI1 is a target for another kinase downstream of ERK1/2 [62]. A later report identified possible MAPK consensus site, including ERK2, within the N-terminus of GLI proteins [63].
Crosstalk between HH-GLI signaling and ERK5 To date no crosstalk has been reported between HH-GLI and ERK5 pathway. However, MEF2C, a well known target of ERK5 [133], has been shown to activate the expression of GLI2 by binding to its promoter during cardiomyogenesis in vitro[134]. Moreover, it is worth pointing out that the majority of experimental data presented in Section 3 have been performed with small molecule kinase inhibitors targeting the ERK1/2 pathway, and these molecules inhibit also MEK5-ERK5. Indeed, PD98059 and U0126, which were initially identified as MEK1/2-specific inhibitors, also affect the MEK5-ERK5 pathway [135], [136], [137]. Moreover, PD184352 (CI-1040), another MEK1/2 inhibitor, decreases the activity of MEK5-ERK5 pathway although at lesser extent [136].
Crosstalk between HH-GLI signaling and JNK JNK are protein kinases that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death. It is increasingly apparent that persistent activation of JNK is also involved in cancer development and progression [138]. Few evidences of an interaction between JNK proteins and HH-GLI pathways have been identified. Below are listed the papers that refer to a crosstalk between JNK and HH signaling in cancer cells or in normal contexts where possible mechanisms of interaction have been described.