Control of Tyrosine Kinase Signalling by Small Adaptors in Colorectal Cancer

Self Cite

The PEAK family pseudokinases are essential components of tyrosine kinase (TK) pathways that regulate cell growth and adhesion; however, their role in human cancer remains unclear. Here, we report an oncogenic activity of the pseudokinase PEAK2 in colorectal cancer (CRC). Notably, high PRAG1 expression, which encodes PEAK2, was associated with a bad prognosis in CRC patients. Functionally, PEAK2 depletion reduced CRC cell growth and invasion in vitro, while its overexpression increased these transforming effects. PEAK2 depletion also reduced CRC development in nude mice. Mechanistically, PEAK2 expression induced cellular protein tyrosine phosphorylation, despite its catalytic inactivity. Phosphoproteomic analysis identified regulators of cell adhesion and F-actin dynamics as PEAK2 targets. Additionally, PEAK2 was identified as a novel ABL TK activator. In line with this, PEAK2 expression localized at focal adhesions of CRC cells and induced ABL-dependent formation of actin-rich plasma membrane protrusions filopodia that function to drive cell invasion. Interestingly, all these PEAK2 transforming activities were regulated by its main phosphorylation site, Tyr413, which implicates the SRC oncogene. Thus, our results uncover a protumoural function of PEAK2 in CRC and suggest that its deregulation affects adhesive properties of CRC cells to enable cancer progression.

Section: Discussionsupporting

confidence: 64%

Oncogenic Signalling of PEAK2 Pseudokinase in Colon Cancer

Lecointre

Fourgous

Montarras

et al. 2022

Self Cite

“…Recently, it was reported that Src tumour activity is under the control of the Src-like adaptor protein SLAP [ 78 , 79 ] ( Figure 2 A,B). Such negative regulatory mechanism mediated by small adaptor proteins was originally described for the Janus Kinase (JAK)/STAT pathway, which it is mediated by the suppressors of cytokine signalling (SOCS) [ 80 ]. SLAP comprises an N-terminal region, similar to the one in Src, and a unique C-terminus with binding affinity to CBL.…”

Section: Sfks In Human Crcmentioning

confidence: 99%

Src Family Tyrosine Kinases in Intestinal Homeostasis, Regeneration and Tumorigenesis

Sirvent

Mevizou

Naim

et al. 2020

Self Cite

Src, originally identified as an oncogene, is a membrane-anchored tyrosine kinase and the Src family kinase (SFK) prototype. SFKs regulate the signalling induced by a wide range of cell surface receptors leading to epithelial cell growth and adhesion. In the intestine, the SFK members Src, Fyn and Yes regulate epithelial cell proliferation and migration during tissue regeneration and transformation, thus implicating conserved and specific functions. In patients with colon cancer, SFK activity is a marker of poor clinical prognosis and a potent driver of metastasis formation. These tumorigenic activities are linked to SFK capacity to promote the dissemination and tumour-initiating capacities of epithelial tumour cells. However, it is unclear how SFKs promote colon tumour formation and metastatic progression because SFK-encoding genes are unfrequently mutated in human cancer. Here, we review recent findings on SFK signalling during intestinal homeostasis, regeneration and tumorigenesis. We also describe the key nongenetic mechanisms underlying SFK tumour activities in colorectal cancer, and discuss how these mechanisms could be exploited in therapeutic strategies to target SFK signalling in metastatic colon cancer.

“…Most CRC tumors have constitutive activation of transcription factors that activate inflammatory pathways, such as NF-κβ and the JAK-STAT pathway [ 25 ]. The JAK-STAT pathway is a major transducer of cytokine-signaling regulating inflammation and immune responses in CRC [ 26 ]. The JAK-STAT pathway is made of eight STAT proteins; primarily STAT-1 and -2 are involved in immune responses [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

“…The JAK-STAT pathway is a major transducer of cytokine-signaling regulating inflammation and immune responses in CRC [ 26 ]. The JAK-STAT pathway is made of eight STAT proteins; primarily STAT-1 and -2 are involved in immune responses [ 26 ]. JAK-STAT activation is a notable characteristic of CMS1 as it displays strong immune activation [ 9 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of Gene Co-Expression Networks Associated with Consensus Molecular Subtype-1 of Colorectal Cancer

Nunez

Young

Griffen

et al. 2021

Colorectal cancer (CRC) is driven in part by dysregulated Wnt, Ras-Raf-MAPK, TGF-β, and PI3K-Akt signaling. The progression of CRC is also promoted by molecular alterations and heterogeneous—yet interconnected—gene mutations, chromosomal instability, transcriptomic subtypes, and immune signatures. Genomic alterations of CRC progression lead to changes in RNA expression, which support CRC metastasis. An RNA-based classification system used for CRC, known as consensus molecular subtyping (CMS), has four classes. CMS1 has the lowest survival after relapse of the four CRC CMS phenotypes. Here, we identify gene signatures and associated coding mRNAs that are co-expressed during CMS1 CRC progression. Using RNA-seq data from CRC primary tumor samples, acquired from The Cancer Genome Atlas (TCGA), we identified co-expression gene networks significantly correlated with CMS1 CRC progression. CXCL13, CXCR5, IL10, PIK3R5, PIK3AP1, CCL19, and other co-expressed genes were identified to be positively correlated with CMS1. The co-expressed eigengene networks for CMS1 were significantly and positively correlated with the TNF, WNT, and ERK1 and ERK2 signaling pathways, which together promote cell proliferation and survival. This network was also aligned with biological characteristics of CMS1 CRC, being positively correlated to right-sided tumors, microsatellite instability, chemokine-mediated signaling pathways, and immune responses. CMS1 also differentially expressed genes involved in PI3K-Akt signaling. Our findings reveal CRC gene networks related to oncogenic signaling cascades, cell activation, and positive regulation of immune responses distinguishing CMS1 from other CRC subtypes.