*2.1.2 Ras/Raf/MEK/ERK pathway*

The Ras/Raf/MEK/ERK pathway, one of the major signaling cascades of the mitogen-activated protein kinase (MAPK) family, plays a key role in cell proliferation, differentiation, motility, and survival [46], and is dysregulated in one-third of human tumors [47]. Activation of this pathway can occur through a variety of mechanisms, including integrin-mediated cell adhesion or activation of membrane RTKs by extracellular stimuli such as growth factors, hormones, cytokines, and mitogens [48]. Although this pathway can be activated by either cell adhesion or growth factors, strong and sustainable ERK activation results from cooperative signaling by both RTKs and integrins [38, 49]. In RTK-mediated signaling, the activation of RTKs leads to the activation of the small GTP-binding protein Ras. Ras recruits Raf kinases to the cell membrane, which in turn activate MEK1 and MEK2, leading to the phosphorylation of ERK1 and ERK2, catalyzed by MEK. Phosphorylated ERK1 and ERK2 translocate to the nucleus and initiate phosphorylation of transcription factors, such as c-Myc, c-fos, Ets, and Elk1 [47]. In contrast to RTK signaling cascades, integrinmediated signal transduction in this pathway is less dependent on Ras and is instead initiated by autophosphorylation of FAK and the formation of FAK-Src complexes [39]. According to the model for adhesion-mediated ERK activation suggested by Yee *et al.*, Shc is phosphorylated by both Src and FAK, which initiates the Shc-Grb2-Sos-Ras cascade, leading to ERK phosphorylation [38].

As mentioned above, Shc phosphorylation by FAK and Src is an important step in integrin-mediated activation of the Ras/Raf/MEK/ERK pathway because only some integrins, including α1β1, α5β1, α6β4, and αvβ3, can recruit Shc to the FAK-Src complex [50]. Similarly, certain integrins, like αvβ6 integrin, play key roles in MEK/ ERK activation which can lead to cancer-associated changes in the Ras/Raf/MEK/ ERK pathway [31, 32]. Studies have shown that ERK activation, induced by thyroid hormone administration, in high αvβ3-expressing ovarian cancer cells enhances cell proliferation and survival, while inhibition of the Ras/Raf/MEK/ERK pathway increased ovarian cancer cell susceptibility to treatment in both chemosensitive and chemoresistant lines [51–54]. In summary, integrin overexpression, notably that of αvβ3 and αvβ6 integrins, may contribute to ovarian cancer progression and resistance to therapies by promoting activation of the Ras/Raf/MEK/ERK pathway cooperatively with RTK-mediated signaling.
