Src family kinases (SFKs) are non-receptor kinases that play a critical role in the pathogenesis of colorectal cancer (CRC). The expression and activity of SFKs are upregulated in patients with CRC. Activation of SFKs promotes CRC cell proliferation, metastases to other organs and chemoresistance, as well as the formation of cancer stem cells (CSCs). The enhanced expression level of Src is associated with decreased survival in patients with CRC. Src-mediated regulation of CRC progression involves various membrane receptors, modulators, and suppressors, which regulate Src activation and its downstream targets through various mechanisms. This review provides an overview of the current understanding of the correlations between Src and CRC progression, with a special focus on cancer cell proliferation, invasion, metastasis and chemoresistance, and formation of CSCs. Additionally, this review discusses preclinical and clinical strategies to improve the therapeutic efficacy of drugs targeting Src for treating patients with CRC.

https://www.mdpi.com/2072-6694/12/5/1339/pdf

Regulation of Src Family Kinases during Colorectal Cancer Development and Its Clinical Implications

Grb2 (Growth factor receptor-bound protein 2) is a key adaptor protein in maintaining the ERK activity via linking Sos1 (Son of sevenless homolog 1) or other proteins to activated RTKs, such as EGFR. Currently, little knowledge is available concerning the post-translational modification (PTM) of Grb2 except for its phosphorylation. Since emerging evidences have highlighted the importance of SUMOylation (Small ubiquitin-related modifier), a reversible PTM, in modulating protein functions, we wondered if Grb2 could be SUMOylated and thereby influences its functions especially involved in the Ras/MEK/ERK pathway. SUMOylation of Grb2 was analyzed with the in vivo SUMOylation assay using the Ni2+-NTA affinity pulldown and the in vitro E.coli-based SUMOylation assay. To test the ERK activity and cell transformation, the murine fibroblast cell line NIH/3T3 and the murine colon cancer cell line CMT-93 were used for the experiments including Grb2 knockdown, ectopic re-expression, cell transformation and migration. Immunoprecipitation (IP) was employed for seeking proteins that interact with SUMO modified Grb2. Xenograft tumor model in mice was conducted to verify that Grb2 SUMOylation regulated tumorigenesis in vivo. Grb2 can be SUMOylated by SUMO1 at lysine 56 (K56), which is located in the linker region between the N-terminal SH3 domain and the SH2 domain. Knockdown of Grb2 reduced the ERK activity and suppressed cell motility and tumorigenesis in vitro and in vivo, which were all rescued by stable ectopic re-expression of wild-type Grb2 but not the mutant Grb2K56R. Furthermore, Grb2 SUMOylation at K56 increased the formation of Grb2-Sos1 complex, which sequentially leads to the activation of Ras/MEK/MAPK pathway. Our results provide evidences that Grb2 is SUMOylated in vivo and this modification enhances ERK activities via increasing the formation of Grb2-Sos1 complex, and may consequently promote cell motility, transformation and tumorigenesis.

/pdf/sumoylation-of-grb2-enhances-the-erk-activity-by-increasing-2nogbmbc1s.pdf

SUMOylation of Grb2 enhances the ERK activity by increasing its binding with Sos1.

Tyrosine phosphorylation of proteins serves as an exquisite switch in controlling several key oncogenic signaling pathways involved in cell proliferation, apoptosis, migration, and invasion. Since protein tyrosine phosphatases (PTPs) counteract protein kinases by removing phosphate moieties on target proteins, one may intuitively think that PTPs would act as tumor suppressors. Indeed, one of the most described PTPs, namely, the phosphatase and tensin homolog (PTEN), is a tumor suppressor. However, a growing body of evidence suggests that PTPs can also function as potent oncoproteins. In this chapter, we provide a broad historical overview of the PTPs, their mechanism of action, and posttranslational modifications. Then, we focus on the dual properties of classical PTPs (receptor and nonreceptor) and dual-specificity phosphatases in cancer and summarize the current knowledge of the signaling pathways regulated by key PTPs in human cancer. In conclusion, we present our perspective on the potential of these PTPs to serve as therapeutic targets in cancer.

Protein tyrosine phosphatases in cancer: friends and foes!

Genomic comparisons between human and distant, non-primate mammals are commonly used to identify cis-regulatory elements based on constrained sequence evolution. However, these methods fail to detect cryptic functional elements, which are too weakly conserved among mammals to distinguish from nonfunctional DNA. To address this problem, we explored the potential of deep intra-primate sequence comparisons. We sequenced the orthologs of 558 kb of human genomic sequence, covering multiple loci involved in cholesterol homeostasis, in 6 nonhuman primates. Our analysis identified 6 noncoding DNA elements displaying significant conservation among primates, but undetectable in more distant comparisons. In vitro and in vivo tests revealed that at least three of these 6 elements have regulatory function. Notably, the mouse orthologs of these three functional human sequences had regulatory activity despite their lack of significant sequence conservation, indicating that they are cryptic ancestral cis-regulatory elements. These regulatory elements could still be detected in a smaller set of three primate species including human, rhesus and marmoset. Since the human and rhesus genome sequences are already available, and the marmoset genome is actively being sequenced, the primate-specific conservation analysis described here can be applied in the near future on a whole-genome scale, to complement the annotation provided by more distant species comparisons.

Detection of Weakly Conserved Ancestral Mammalian Regulatory Sequences by Primate Comparisons

Stepping out of the shadows: Oncogenic and tumor-promoting protein tyrosine phosphatases.

Receptor protein tyrosine phosphatase α (RPTPα)‐mediated Src activation is required for survival of tested human colon and oestrogen receptor‐negative breast cancer cell lines. To explore whether mutated RPTPα participates in human carcinogenesis, we sequenced RPTPα cDNAs from five types of human tumours and found splice mutants in ∼30% of colon, breast, and liver tumours. RPTPα245, a mutant expressed in all three tumour types, was studied further. Although it lacks any catalytic domain, RPTPα245 expression in the tumours correlated with Src tyrosine dephosphorylation, and its expression in rodent fibroblasts activated Src by a novel mechanism. This involved RPTPα245 binding to endogenous RPTPα (eRPTPα), which decreased eRPTPα–Grb2 binding and increased eRPTPα dephosphorylation of Src without increasing non‐specific eRPTPα activity. RPTPα245–eRPTPα binding was blocked by Pro210 → Leu/Pro211 → Leu mutation, consistent with the involvement of the structural ‘wedge’ that contributes to eRPTPα homodimerization. RPTPα245‐induced fibroblast transformation was blocked by either Src or eRPTPα RNAi, indicating that this required the dephosphorylation of Src by eRPTPα. The transformed cells were tumourigenic in nude mice, suggesting that RPTPα245‐induced activation of Src in the human tumours may have contributed to carcinogenesis.

/pdf/activation-of-src-and-transformation-by-an-rptpa-splice-zwz33zx42j.pdf

Activation of Src and transformation by an RPTPα splice mutant found in human tumours

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Activation of Src and transformation by an RPTPα splice mutant found in human tumours