Fak/Src signaling in human intestinal epithelial cell survival and anoikis: Differentiation state‐specific uncoupling with the PI3‐K/Akt‐1 and MEK/Erk pathways

Abstract

Human intestinal epithelial cell survival and anoikis are distinctively regulated according to the state of differentiation. In the present study, we analyzed the roles of focal adhesion kinase (Fak)/Src signaling to the PI3-K/Akt-1 and mitogen-activated protein kinase (MEK)/extracellular regulated kinases (Erk) pathways, within the context of such differentiation-state distinctions. Anoikis was induced by inhibition of beta1 integrins (antibody blocking), inhibition of Fak (pharmacologic inhibition or overexpression of dominant negative mutants), or by maintaining cells in suspension. Activation parameters of Fak, Src, Akt-1, and Erk1/2 were analyzed. Activities of Src, Akt-1, or Erk1/2 were also blocked by pharmacological inhibition or by overexpression of dominant-negative mutants. We report that: (1) the loss or inhibition of beta1 integrin binding activity causes anoikis and results in a down-activation of Fak, Src, Akt-1, and Erk1/2 in both undifferentiated, and differentiated cells; (2) the inhibition of Fak likewise causes anoikis and a down-activation of Src, Akt-1, and Erk1/2, regardless of the differentiation state; (3) Src, PI3-K/Akt-1, and MEK/Erk contribute to the survival of differentiated cells, whereas MEK/Erk does not play a role in the survival of undifferentiated ones; (4) the inhibition/loss of beta1 integrin binding and/or Fak activity results in a loss of Src engagement with Fak, regardless of the state of differentiation; and (5) Src contributes to the activation of both the PI3-K/Akt-1 and MEK/Erk pathways in undifferentiated cells, but does not influence PI3-K/Akt-1 in differentiated ones. Hence, Fak/Src signaling to the PI3-K/Akt-1 and MEK/Erk pathways undergoes a differentiation state-specific uncoupling which ultimately reflects upon the selective engagement of these same pathways in the mediation of intestinal epithelial cell survival.

Transforming Growth Factor-β Stimulates Intestinal Epithelial Focal Adhesion Kinase Synthesis via Smad- and p38-Dependent Mechanisms

“…In zone 2, adjacent to the ulcer, FAK induction by TGF-␤ via Smad and p38 signaling may prevent anoikis or may induce differentiation to either a more migratory phenotype or one that is more sensitive to activation by other locally produced factors ( Figure 13). 86,87 Modulation of FAK, Smad, and p38 signaling might therefore be expected to modulate TGF-␤ effects, but this is beyond the scope of the current investigation and awaits future study.…”

Synergistically Anti-metastatic Effect of 5-Flourouracil on Colorectal Cancer Cells via Calcium-mediated Focal Adhesion Kinase Proteolysis

“…FAK is involved in SRC-mediated phosphorylation, which is necessary for activation of proliferation signals, such as RAS (19). As a result, FAK regulates many growth factor signaling pathways that are important for the survival of human cancer cells (19).…”

“…FAK is involved in SRC-mediated phosphorylation, which is necessary for activation of proliferation signals, such as RAS (19). As a result, FAK regulates many growth factor signaling pathways that are important for the survival of human cancer cells (19). Additionally, complexes of FAK with SRC and phosphatidylinositol 3-kinase (PI3K) are well known differential regulators of cell migration (20 roles in cancer cell invasion and migration (21).…”

Molecular mechanism of peritoneal dissemination in gastric cancer

“…Cancer cells develop anoikis resistance via several mechanisms, including changes in integrin repertoire expression, induction of EMT, oncogene activation, and adaption of their metabolism [45][46][47] . In gastrointestinal cancers, the PI3K/Akt [48][49][50] and PTEN/PI3K/NF-κB/FAK pathways [51,52] are involved in the formation of PD and anoikis resistance. FAK is a key integrin signaling molecule involved in cell survival pathways [51,52] .…”

“…In gastrointestinal cancers, the PI3K/Akt [48][49][50] and PTEN/PI3K/NF-κB/FAK pathways [51,52] are involved in the formation of PD and anoikis resistance. FAK is a key integrin signaling molecule involved in cell survival pathways [51,52] . Moreover, the CXCL12/CXCR4 pathway can induce EMT [53,54] and is associated with PD and anoikis resistance [55,56] in multiple human cancers.…”