All Good Things Must End: Termination of Receptor Tyrosine Kinase Signal

Abstract

Receptor tyrosine kinases (RTKs) are membrane receptors that regulate many fundamental cellular processes. A tight regulation of RTK signaling is fundamental for development and survival, and an altered signaling by RTKs can cause cancer. RTKs are localized at the plasma membrane (PM) and the major regulatory mechanism of signaling of RTKs is their endocytosis and degradation. In fact, RTKs at the cell surface bind ligands with their extracellular domain, become active, and are rapidly internalized where the temporal extent of signaling, attenuation, and downregulation are modulated. However, other mechanisms of signal attenuation and termination are known. Indeed, inhibition of RTKs’ activity may occur through the modulation of the phosphorylation state of RTKs and the interaction with specific proteins, whereas antagonist ligands can inhibit the biological responses mediated by the receptor. Another mechanism concerns the expression of endogenous inactive receptor variants that are deficient in RTK activity and take part to inactive heterodimers or hetero-oligomers. The downregulation of RTK signals is fundamental for several cellular functions and the homeostasis of the cell. Here, we will review the mechanisms of signal attenuation and termination of RTKs, focusing on FGFRs.

Anti-ROR1 CAR-T cells: Architecture and performance

“…Receptors with tyrosine kinase activity and their ligands regulate several cellular processes, such as development and survival. However, they may also participate in the emerging of diseases, such as cancer [reviewed in (62)]. This receptor group includes the tyrosine kinase-like orphan receptors (RORs) family.…”

“…SUPPLEMENTARY FIGURE 2 ROR1 RNA expression in normal tissues. The summary shows the consensus data bases on normalized expression (nTPM) values from two different sources, the human protein atlas RNA-seq data and RNA-seq data from the genotype-tissue expression project (https://www.proteinatlas.org/ENSG00000185483-ROR1/tissue) (62).…”

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

“…In fact, it has been established that a hormone-GF generated signal and underlying cellular effect following transducing receptor activation tends to temper down within a relatively short time due to the signal-induced parallel downregulation of the stimulated receptor expression, also known as a negative hormone/GF feedback ( 1 ). Such acute effect has been associated to ligand-induced subcellular sequestration of the activated trans-membrane receptor through multiple mechanisms, including endocytosis and lysosomal degradation ( 2 , 3 ). More recently, the advancement in our understanding of ubiquitin-targeted degradation processes has added an additional mechanism responsible for hormone-GF negative feedbacks at the cellular level, namely, the acute and specific RTK targeting by means of ubiquitin-flagging enzymes known as E3 ubiquitin ligases like CBL (reviewed in ( 4 ).…”

Cell fate‐inducing CARs orthogonally control multiple signaling pathways

“…[ 1–3 ] Among the receptors, transmembrane receptors receive the specific ligands in the extracellular domain, undergo conformational changes, and activate downstream signaling pathways to control cell fates. [ 4–6 ] Thus, transmembrane receptors play important roles in responding to extracellular signals to adapt cells to extracellular environmental changes through intracellular signal transduction.…”

“…[1][2][3] Among the receptors, transmembrane receptors receive the specific ligands in the extracellular domain, undergo conformational changes, and activate downstream signaling ABBREVIATIONS: aiCAR, apoptosis-inducing CAR; CAR, chimeric antigen receptor; cfiCAR, cell fate-inducing CAR; DNP, dinitrophenol; FL, fluorescein; IL-3, interleukin-3; IRES, internal ribosomal entry site; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; piCAR, proliferation-inducing CAR; RANK, receptor activator of nuclear factor κB; scFv, single-chain Fv; STAT, signal transducers and activators of transcription pathways to control cell fates. [4][5][6] Thus, transmembrane receptors play important roles in responding to extracellular signals to adapt cells to extracellular environmental changes through intracellular signal transduction.…”