Signal Transduction
Non-receptor Kinases & Phosphatases
Signal transduction proteins are activated by the addition of phosphate groups (‘phosphorylation’) by proteins called kinases, and deactivated by the removal of the same phosphate groups (‘dephosphorylation’) by proteins called phosphatases. Aberrantly activated kinases or deactivated phosphatases result in carcinogenesis because they deregulate the normal controls on cell processes.
Introduction
Signal transduction begins with the phosphorylation of a receptor kinase on the cell surface, which acts as a sensor of the cell’s environment, and is activated by the binding of specific extracellular ‘ligands’ (hormones, growth factors, or cytokines). The proteins in the signal transduction pathways are then sequentially activated by non-receptor kinases, which phosphorylate certain amino acids (tyrosines, serines, or threonines) in the signaling protein’s sequence. Frequently the ultimate targets of the signal transduction pathways are specific proteins in the nucleus that are called ‘transcription factors’. These transcription factors cause certain genes to be ‘expressed’ (the gene is transcribed into RNA, which is then translated into a protein) in order for the cell to respond to its environment, as directed by the receptor. The response may be for the cell to undergo growth, proliferation, migration, differentiation (the structure and/or function of the cell is changed), or apoptosis (cell suicide). When the receptor senses that the cell no longer needs to respond to the environment, the proteins in the signal transduction pathway driving the process are dephosphorylated, causing the signal transduction and the gene expression to stop.
Cancer may subvert normal cell processes by causing kinases to be constitutively activated, thus continuously phosphorylating signal transduction pathways, or by causing phosphatases to be deactivated, thus removing the normal control for the cessation of signal transduction.
LICR investigators and Affiliates have made seminal contributions to several fields of study relating to non-receptor kinases and phosphatases:
- PI3K - The phosphoinositide 3-kinases (PI3Ks) regulate several key signal transduction pathways controlling vital cell processes that are frequently implicated in carcinogenesis through the phosphorylation of lipid molecules. LICR investigators are studying different PI3K enzymes, and developing drugs that specifically inhibit these enzymes for potential cancer therapies.
- PTEN - The PTEN phosphatase is an agonist of PI3Ks, meaning that it dephosphorylates lipid molecules that are phosphorylated by PI3Ks. PTEN has a central role in controlling cell processes that are implicated in carcinogenesis. PTEN is frequently inactivated, due to gene mutation, in several cancers.
- JAK/STAT - The Janus-activated kinases (JAK) activate the signal transducers of transcription (STAT) family, which plays a critical role in regulating the body’s immune response. STATs can also be activated by the platelet-derived growth factor receptor (PDGFR), the epidermal growth factor receptor (EGFR).
- SHP - The SHP phosphatases have an important function in regulating signal transduction in lymphocytes, and the loss of SHP has been associated with the development of leukemias and lymphomas. SHP phosphatases have also been shown to be agonists of the JAKs pathway, and thus down-regulation of SHP results in increased JAK/STAT activity.
- Src - The Src kinases, which have been shown to be activated in several types of cancer including breast, colon, and pancreatic carcinomas, are downstream of the epidermal growth factor receptor (EGFR), the platelet-derived growth factor receptor (PDGFR), and the vascular endothelial growth factor (VEGFR). The role of Src downstream of VEGFR is of particular interest for the investigators of the LICR Angiogenesis and Lymphangiogenesis Program.