Ults [4,54], our data suggest that C3G plays a key role in the regulation of CML cell adhesion as (i) C3G silencing decreases adhesion to fibronectin, (ii) changes in C3G expression alters the levels of expression and activation of FA proteins, such as FAK, paxillin, CrkL, Cbl and integrin 5, and (iii) C3G silencing increases the interaction between CrkL and paxillin (difficult to observe in control cells) and decreases CrkL interaction with Bcr-Abl. This is relevant, since aberrant interaction between CrkL and paxillin is induced by Bcr-Abl in CML cells [46]. Therefore, p140C3G could act as a negative regulator of BcrAbl-induced abnormal adhesion. A role for C3G in the formation or stabilization of integrin 1- and paxillinpositive FAs has also been described in MEFs [54]. 2-Bromo-1,3-difluoro-4-nitrobenzene In agreement with other studies [55], Abi1 is a positive regulator of adhesion to fibronectin. In contrast, our results on Cbl are different from previous reports. Cbl negatively regulates cell adhesion in most systems by targeting 5-integrin, CrkL and FAK for ubiquitination [56,57]. However, our results reveal a positive role for Cbl in CML cell adhesion, as Cbl silencing impaired adhesion of CML cells. p130Cas seems to exert a negative effect in CML adhesion, in agreement with its role in migration and invasion [58,59]. Regarding 3-Amino-1H-indazole-4-carbonitrile title=View Abstract(s)">PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/8086425 p38 we have contradictory results as p38 knock-down decreased adhesion to fibronectin, but also increased the levels and/ or activity of some FA proteins such as paxillin. The decreased adhesion observed in p38 silenced K562 cells point out to a positive regulation of CML adhesion by p38, according to the role proposed for p38 in adhesion in human melanoma cells [60] and in Karpas 299 lymphoma cells based on the effect of the p38/?inhibitor SB203580 [61]. However, results derived from studies performed with p38 knock-out cells indicates that p38 plays a negative role in adhesion in mouse embryonic stem cells [18] and in embryonic cardiomyocytes [62]. Differences between cell types might account for these distinct functions of p38 in adhesion. It would be also possible that p38 could play a different role in normal and tumoral cells as adhesion is altered in tumoral cells. In contrast to the reduced adhesion found in p38 silenced K562 cells, either p38 knockdown or SB203580 treatment induced an increase in the expression of FA proteins, mainly paxillin, integrin 5 and CrkL, as well asan increase in phospho-paxillin, which is normally associated with increased adhesion. This effect PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/13485127 was stronger in cells attached to fibronectin. Similar results were observed by Guo and coworkers [18]. A plausible explanation is that the increase in the expression of FA proteins induced by p38 silencing alters the stoichiometry of the FA complexes, leading to adhesion defects likely due to the impairment of assembly and disassembly of focal adhesion complexes. Additionally, it should be noted that adhesion experiments were performed under serumdeprivation, which induces the activation of p38 and other p38 isoforms (mainly ? [62,63] and can alter the activity of other signaling molecules involved in adhesion such as Rac1 [62]. All this would lead to a potential imbalance of different signaling pathways that could induce a decrease in adhesion. Finally, the fact that double C3G/ p38 silenced cells present a similar decreased adhesion to fibronectin that the single knock-down clones, suggests that both proteins could participate in the same signaling pathway regul.