On the other hand, the role of SHP-2 in multiple kinase pathways – including MAPK, JAK/STAT, and IGF – is well established.
In other NSCLC cases which are not driven by EGFR mutations, both EGFR- and IGF1R-mediated pathways have been demonstrated to have altered signaling, as illustrated by the DNA sequencing studies of NSCLC clinical specimens, where multiple kinase pathways were found to be changed.
The activation of multiple kinase signalling pathways leads to transcriptional effects independent of nucleolar RARs via transcription factors that lie at the end of these signalling cascades (Al Tanoury et al, 2013; see Figure 2).
In addition to the above, both superoxide and hydrogen peroxide contribute to endothelium-independent constriction through activation of multiple protein kinase pathways.
FAK promotes cell migration via the activation of multiple signaling pathways involving kinases, or by phosphorylation of other FA components26.
It is tempting to speculate that this expression signature indicates a state of a parallel, synergistic activation of multiple receptor pathways (receptor tyrosine kinases, G-protein-coupled receptors and nuclear transcription factors), which vastly promote tumour cell proliferation and angiogenesis in the tumour stroma.
Loss of merlin in cultured Schwann cells leads to altered morphology, enhanced proliferation and over activation of multiple signalling pathways including Rac GTPase, extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and phosphatidyl inositol-3 kinase (PI-3 kinase) MAP kinase pathways (Shaw et al., 2001; Kaempchen et al., 2003; Ammoun et al., 2008).
For example, multiple components of the PI3 kinase pathway were translationally repressed during mitosis.
These data indicate that chemoattractant receptors induce chemokine production in HMC-1 cells with a selectivity that depends on the level of receptor expression, the length of their signaling time, and the synergistic interaction of multiple signaling pathways, including extracellular signal-regulated kinase phosphorylation, sustained Ca(2+) mobilization and NFAT activation.
