scholarly journals mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

2017 ◽  
Vol 24 (6) ◽  
pp. 1045-1062 ◽  
Author(s):  
Aikaterini Lampada ◽  
James O'Prey ◽  
Gyorgy Szabadkai ◽  
Kevin M Ryan ◽  
Daniel Hochhauser ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Receptor Tyrosine Kinase ◽  
Colorectal Cancer Cells ◽  
Kinase Phosphorylation

scholarly journals Cell surface integrin α5ß1 clustering negatively regulates receptor tyrosine kinase signaling in colorectal cancer cells via glycogen synthase kinase 3

2021 ◽  
Author(s):  
Alina Starchenko ◽  
Ramona Graves-Deal ◽  
Douglas Brubaker ◽  
Cunxi Li ◽  
Yuping Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factors ◽  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Receptor Tyrosine Kinase ◽  
Negative Regulator ◽  
Mouse Tumor ◽  
Functional Responses ◽  
Colorectal Cancer Cells

Abstract As a key process within the tissue microenvironment, integrin signaling can influence cell functional responses to growth factor stimuli. We show here that clustering of integrin α5ß1 at the plasma membrane of colorectal cancer-derived epithelial cells modulates their ability to respond to stimulation by receptor tyrosine kinase (RTK)-activating growth factors EGF, NRG and HGF, through GSK3-mediated suppression of Akt pathway. We observed that integrin α5ß1 is lost from the membrane of poorly organized human colorectal tumors and that treatment with the integrin-clustering antibody P4G11 is sufficient to induce polarity in a mouse tumor xenograft model. While adding RTK growth factors (EGF, NRG and HGF) to polarized colorectal cancer cells induced invasion and loss of monolayer formation in 2D and 3D, this pathological behavior could be blocked by P4G11. Phosphorylation of ErbB family members as well as MET following EGF, NRG and HGF treatment was diminished in cells pretreated with P4G11. Focusing on EGFR, we found that blockade of integrin α5ß1 increased EGFR phosphorylation. Since activity of multiple downstream kinase pathways were altered by these various treatments, we employed computational machine learning techniques to ascertain the most important effects. Partial least-squares discriminant analysis identified GSK3 as a major regulator of EGFR pathway activities influenced by integrin α5ß1. Moreover, we used partial correlation analysis to examine signaling pathway crosstalk downstream of EGF stimulation and found that integrin α5ß1 acts as a negative regulator of the AKT signaling cascade downstream of EGFR, with GSK3 acting as a key mediator. We experimentally validated these computational inferences by confirming that blockade of GSK3 activity is sufficient to induce loss of polarity and increase of oncogenic signaling in the colonic epithelial cells.

scholarly journals N‑glycosylation and receptor tyrosine kinase signaling affect claudin‑3 levels in colorectal cancer cells

2020 ◽  
Author(s):  
Amelia P�rez ◽  
J�ssica Andrade‑Da‑Costa ◽  
Waldemir De Souza ◽  
Michelle De Souza Ferreira ◽  
Mariana Boroni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Receptor Tyrosine Kinase ◽  
Kinase Signaling ◽  
Tyrosine Kinase Signaling ◽  
Colorectal Cancer Cells

scholarly journals Liver Kinase B1 Expression Promotes Phosphatase Activity and Abrogation of Receptor Tyrosine Kinase Phosphorylation in Human Cancer Cells

2013 ◽  
Vol 289 (3) ◽  
pp. 1639-1648 ◽  
Author(s):  
Imoh S. Okon ◽  
Kathleen A. Coughlan ◽  
Ming-Hui Zou
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Receptor Tyrosine Kinase ◽  
Egf Receptor ◽  
Liver Kinase B1 ◽  
Kinase Phosphorylation

Aberrant receptor tyrosine kinase phosphorylation (pRTK) has been associated with diverse pathological conditions, including human neoplasms. In lung cancer, frequent liver kinase B1 (LKB1) mutations correlate with tumor progression, but potential links with pRTK remain unknown. Heightened and sustained receptor activation was demonstrated by LKB1-deficient A549 (lung) and HeLaS3 (cervical) cancer cell lines. Depletion (siRNA) of endogenous LKB1 expression in H1792 lung cancer cells also correlated with increased pRTK. However, ectopic LKB1 expression in A549 and HeLaS3 cell lines, as well as H1975 activating-EGF receptor mutant lung cancer cell resulted in dephosphorylation of several tumor-enhancing RTKs, including EGF receptor, ErbB2, hepatocyte growth factor receptor (c-Met), EphA2, rearranged during transfection (RET), and insulin-like growth factor I receptor. Receptor abrogation correlated with attenuation of phospho-Akt and increased apoptosis. Global phosphatase inhibition by orthovanadate or depletion of protein tyrosine phosphatases (PTPs) resulted in the recovery of receptor phosphorylation. Specifically, the activity of SHP-2, PTP-1β, and PTP-PEST was enhanced by LKB1-expressing cells. Our findings provide novel insight on how LKB1 loss of expression or function promotes aberrant RTK signaling and rapid growth of cancer cells.

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