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Integrins and anoikis
1Burnham Institute, La Jolla Cancer Research Center, CA 92037, USA. sfrisch@ljcrf.edu
Abstract:
The loss of integrin-mediated cell-matrix contact induces apoptosis ('anoikis') in certain cell types. Recently it has been shown that protein kinase signaling pathways control anoikis both positively and negatively. Focal adhesion kinase, when activated by integrins, can suppress anoikis. Phosphatidylinositol 3-kinase and the AKT oncoprotein may mediate the anoikis-suppressing effects of focal adhesion kinase. Conversely, the stress-activated protein kinase/Jun amino-terminal kinase pathway promotes anoikis. Latest results indicate that caspase-mediated cleavage of the first component of this latter pathway, MEKK-1, may trigger activation of this pathway in anoikis. In addition, certain integrins may regulate bcl-2 expression levels, possibly adjusting the threshold for anoikis.
Insights
Cell detachment triggers anoikis, a form of apoptosis regulated by protein kinases. Focal adhesion kinase signaling suppresses anoikis, while stress-activated protein kinase pathways promote it, influencing cell survival.
Area of Science:
- Cell biology
- Molecular signaling
- Apoptosis research
Background:
- Anoikis, or apoptosis induced by loss of cell-matrix adhesion, is a critical process in multicellular organisms.
- Protein kinase signaling pathways play a dual role in regulating anoikis, acting as both positive and negative regulators.
- Integrin-mediated cell-matrix interactions are key initiators of signaling cascades that influence anoikis.
Purpose of the Study:
- To elucidate the molecular mechanisms by which protein kinase pathways regulate anoikis.
- To identify key signaling molecules and pathways involved in the induction or suppression of anoikis.
- To explore the role of integrins and their downstream effectors in controlling the threshold for anoikis.
Main Methods:
- Investigated the role of focal adhesion kinase (FAK) activation by integrins in anoikis suppression.
- Examined the involvement of phosphatidylinositol 3-kinase (PI3K) and AKT in mediating FAK's anti-anoikis effects.
- Analyzed the pro-anoikis activity of the stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK) pathway.
- Studied the caspase-mediated cleavage of MEKK-1 as a potential trigger for SAPK/JNK activation in anoikis.
- Assessed the influence of integrins on bcl-2 expression levels as a modulator of anoikis.
Main Results:
- Focal adhesion kinase activation by integrins suppresses anoikis, potentially through PI3K/AKT signaling.
- The SAPK/JNK pathway promotes anoikis, with evidence suggesting MEKK-1 cleavage by caspases initiates this pathway.
- Integrin engagement can modulate bcl-2 expression, affecting the cellular threshold for anoikis induction.
- Specific protein kinase pathways are identified as critical regulators of anoikis.
Conclusions:
- Protein kinase signaling networks are central to the regulation of anoikis.
- Integrin-mediated signaling and downstream pathways like FAK/PI3K/AKT and SAPK/JNK are key determinants of anoikis sensitivity.
- Targeting these pathways may offer strategies to control anoikis in various physiological and pathological contexts.