Over-expression by degradation rescue of RTKs via cancer-secreted autocrine growth factors: a Phospho-degron-driven actionable layer of post-translational regulation?

Abstract

Recently published work provide the first known evidence of a malignancy-associated regulatory mechanism, functionally connecting a phospho-regulated degron domain embedded in a receptor tyrosine kinase (RTK), with its ectopic expression in cancer, conditional to a specific autocrine growth factor signal. Mechanistically, the growth factor-triggered phosphorylation inhibits the degron domain present in the regulated RTK, blocking access to a specific degradation complex. This ultimately rescues the RTK from rapid ubiquitin-proteasome-system-mediated degradation and, most importantly, causes its cellular overexpression. This mechanism, which has been here assigned the new functional name “Over-Expression by Degradation Rescue” (OEDR), provides an additional layer and potentially preferential tool for the control of RTKs expression in cancer, in addition to other mechanisms acting at the transcriptional and messenger transcript stabilization levels. We propose this newly defined phosphorylation/ubiquitination switch-dependent signal to bear wider unexploited relevance in cell biology and human pathophysiology. The recently identified mechanism underlying an OEDR-regulated RTK is discussed herein in the context of physiological endocrine circuits and cancer.

Autocrine IGF-II-Associated Cancers: From a Rare Paraneoplastic Event to a Hallmark in Malignancy

“…Published work on the Insulin/IGF ligands and receptorial system in cancer provides an emerging landscape with a distinctive role for cancer-secreted IGF-II and its autocrine effects. The latest findings associating IGF-II autocrine loops in cancer to the Over-Expressionby-Degradation Rescue (OEDR) of an IGF-II signal-targeted angiogenic/oncogenic RTK [19] adds an underscored mechanistic tool used by cancer-secreted IGF-II to exert its tumorigenic effects. Our present work is compliant with a differential role and significance of endocrine IGFs compared to those acting in the extracellular environment during tumorigenesis.…”

“…Therefore, the old view that the IGF-I receptor (IGF-IR) would exclusively mediate growth, proliferative, and anti-apoptotic signals from IGF-I and IGF-II while the Insulin receptor (IR) would mediate metabolic actions in response to insulin is obsolete and does not reflect the actual biology of IGFs in cancer, despite being perpetuated till recently. Additionally, even in the presence of a partially redundant number of co-targeted intra-cellular molecules, the evidence of distinctive intracellular targeting abilities mediated by the two receptors (IGF-IR and IR A ) upon activation by the same autocrine ligand (IGF-II) (as for the autocrine IGF-II/IR A -mediated degradation rescue of EphB4 [19,74]) or the different targeting ability of individual Insulin/IGFs through same receptor (IR A ) [25,75] has been increasingly demonstrated. Furthermore, a number of published findings have identified Insulin/IGF-ligand-dependent and hetero-dimeric receptor tyrosine kinase type-dependent signals and underlying differentially regulated targets [25,71], supporting the view that a number of distinctive signals are indeed generated in the same cell according to the contextual ligands and receptors co-expression [16,23].…”

“…The timeline of key discoveries connecting IGF-II to paraneoplastic hypoglycemia and proving its unique biological features are conveyed in Figure 1. [2]; Doege 1930 [3]; Potter 1930 [4]; Daughaday et al, 1981 [13]; Daughaday 1989 [6]; Rogler et al, 1994;[14]; Christifori et al, 1994 [15]; Frasca et al, 1999 [16]; Ritter et al, 2002 [17]; Haley et al, 2012 [18]; Dynkevich et al, 2013 [5]; Salia et al, 2023 [19]. [2]; Doege 1930 [3]; Potter 1930 [4]; Daughaday et al, 1981 [13]; Daughaday 1989 [6]; Rogler et al, 1994;[14]; Christifori et al, 1994 [15]; Frasca et al, 1999 [16]; Ritter et al, 2002 [17]; Haley et al, 2012 [18]; Dynkevich et al, 2013 [5]; Salia et al, 2023 [19].…”