Cell adhesion tunes inflammatory TPL2 kinase signal transduction.
Maria VougioukalakiKonstantina GeorgilaEmmanouil I AthanasiadisAristides G EliopoulosPublished in: Cellular and molecular life sciences : CMLS (2022)
Signaling through adhesion-related molecules is important for cancer growth and metastasis and cancer cells are resistant to anoikis, a form of cell death ensued by cell detachment from the extracellular matrix. Herein, we report that detached carcinoma cells and immortalized fibroblasts display defects in TNF and CD40 ligand (CD40L)-induced MEK-ERK signaling. Cell detachment results in reduced basal levels of the MEK kinase TPL2, compromises TPL2 activation and sensitizes carcinoma cells to death-inducing receptor ligands, mimicking the synthetic lethal interactions between TPL2 inactivation and TNF or CD40L stimulation. Focal Adhesion Kinase (FAK), which is activated in focal adhesions and mediates anchorage-dependent survival signaling, was found to sustain steady state TPL2 protein levels and to be required for TNF-induced TPL2 signal transduction. We show that when FAK levels are reduced, as seen in certain types of malignancy or malignant cell populations, the formation of cIAP2:RIPK1 complexes increases, leading to reduced TPL2 expression levels by a dual mechanism: first, by the reduction in the levels of NF-κΒ1 which is required for TPL2 stability; second, by the engagement of an RelA NF-κΒ pathway that elevates interleukin-6 production, leading to activation of STAT3 and its transcriptional target SKP2 which functions as a TPL2 E3 ubiquitin ligase. These data underscore a new mode of regulation of TNF family signal transduction on the TPL2-MEK-ERK branch by adhesion-related molecules that may have important ramifications for cancer therapy.
Keyphrases
- pi k akt
- extracellular matrix
- signaling pathway
- rheumatoid arthritis
- cell adhesion
- cell death
- single cell
- cell proliferation
- cancer therapy
- poor prognosis
- oxidative stress
- diabetic rats
- cell migration
- gene expression
- tyrosine kinase
- stem cells
- drug delivery
- drug induced
- lps induced
- escherichia coli
- machine learning
- binding protein
- cystic fibrosis
- electronic health record
- deep learning
- squamous cell carcinoma
- big data
- lymph node metastasis
- bone marrow
- candida albicans
- data analysis
- heat shock protein
- protein protein