FAK Acts as a Suppressor of RTK-MAP Kinase Signalling in Drosophila melanogaster Epithelia and Human Cancer Cells

Abstract

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours.

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

“…Consistent with this idea, Ret expression leads to both Src42A and Fak phosphorylation, but we find that the two kinases have opposing effects on proliferation: Src42A promotes proliferation downstream of Ret, whereas Fak blocks it. Hence, despite the fact that blocking Fak function may represent a therapeutic opportunity in some cancers (Ashton et al , 2010; Lee et al , 2015), our findings are more aligned with a previous study (Macagno et al , 2014) that suggested that, at least in the context of Ret‐driven tumorigenesis, Fak can act as a tumour suppressor. In future, it will also be of interest to explore how the Ras/Raf/Erk pathway, activated by Ret in other contexts and previously shown to affect ISC proliferation in flies (Buchon et al , 2010; Biteau & Jasper, 2011; Jiang et al , 2011), intersects with Src/Fak/Wg signalling in response to Ret activation.…”

“…Both Ret and Src kinases can phosphorylate Fak in vitro (Erpel & Courtneidge, 1995;Plaza-Menacho et al, 2011). In the context of gain-of-function Ret mutations, different studies have reached opposite conclusions regarding the ability of Fak to enhance or suppress Ret-driven neoplasia (Panta et al, 2004;Plaza-Menacho et al, 2011;Sandilands et al, 2012;Macagno et al, 2014). Concurrent with Wg induction and pSrc upregulation, Ret expression in adult intestinal progenitors led to a small but detectable induction of pFak ( Fig 4F).…”

Modeling invasion patterns in the glioblastoma battlefield

“…To determine the molecular changes at the GB front in relation with the activity of integrins, we immunostained GB brain samples with Talin, a mediator of integrin adhesivity (45), and with Focal Adhesion Kinase (FAK), a cytoplasmic Tyrosine kinase involved in signaling and cytoskeleton dynamics associated to integrin activity (46,47). We analyzed confocal mi- To confirm the functional contribution of integrins to GB progression and validate these suggestions, we used specific RNAi constructs to knockdown myospheroid (mys), the Drosophila Integrin B subunit, or rhea, the Drosophila Talin, two key players for integrin function.…”

Focal Adhesion Kinase–Mediated Activation of Glycogen Synthase Kinase 3β Regulates IL-33 Receptor Internalization and IL-33 Signaling

“…John et al and Bianchi et al have shown that inhibition of GSK3β decreased phosphorylation of FAK during cell spreading and migration (44, 45). FAK has been known to regulate the recycling of receptor tyrosine kinases back to the plasma membrane (46). This is the first report regarding the role of FAK in the regulation of receptor internalization.…”