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.

Keywords: RTK; UPS; UbE3L; degron; gf; pDegron; paDegron; piDegron.

Figure 1

Layers of hormone/growth factor (GF) regulation. Key concept to the mechanism of physiologic and pathologic events regulating hormones and growth factors function is the point of production/secretion (where the hormone/GF-producing cell is located) and the point of specific targeting (where the hormone/GF receptor and transducing effector-bearing cell/tissue is located). In this regard, three layers or modes of action have been described. These layers include the endocrine level (pink arrows), the paracrine level (purple arrows) and the autocrine level (red arrow). The implications of these established regulatory loops with regards to GF-induced OEDR of RTKs are discussed in the text.

Figure 2

Essential mechanism underlying phospho-activated (pa)Degron-mediated expression versus phospho-inhibited (pi)Degron-mediated expression of a cellular RTK (graphic summary). (A), pattern of paDegron-mediated RTK expression according to Hormone/GF signal status. The function of a pa Degron domain in an RTK is compatible with an endocrine/paracrine negative hormone/GF loop where the signal causes downregulation of the activated (target) receptor (for eg that mediated by CBL) [(A) upper workflow]. Under reduced hormone/GF levels, the paDegron is generally not made accessible to the UbE3L [(A) lower workflow]. (B), pattern of piDegron-mediated RTK expression according to Hormone/GF signal status. On the opposite, the piDegron function fits the function of a positive feedback loop [(B) upper workflow] by extending the RTK expression lifespan and overall protein levels. This type of mechanism is here defined as Over-Expression by Degradation Rescue (OEDR). Under such circuit, reduced or inhibited autocrine signal leads to rapid clearance of the controlled RTK [(B) lower workflow]. This type of mechanism (OEDR) entails the presence of a piDegron in an RTK and is hypothesized by the authors to play a wider role in other positive feedback loops.