Cell signaling
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P182-183
2025-11-02
51
To decide whether to proliferate, cells scan their environment with the help of cell surface receptors such as receptor tyrosine kinases (RTKs) that bind extracellular ligands and activate signaling path ways. RTKs become activated by ligand-stabilized dimerization that allows autophosphorylation. The intracellular phosphotyrosine residues are recognized by SH2 (Src homology 2) or PTB (phosphotyrosine-binding) protein domains, leading to the recruitment of signaling effectors and formation of signaling complexes. In turn, these complexes permit activation of signaling pathways, such as rat sarcoma virus (RAS)–mitogen-activated protein kinase (MAPK), PI3K, and phospholipase Cγ (PLCγ). Together, these signaling path ways stimulate cell proliferation (Fig. 1).
Fig1. SIGNALING PATHWAYS, SUCH AS THE RAS-MAPK PATHWAY, CONTROL CELL CYCLE ENTRY. (See text for details and names of abbreviated items.) Cells scan their environment with the help of cell surface receptors such as receptor tyrosine kinases (RTKs). When RTKs become activated by ligand-stabilized dimerization, they can induce signaling pathways, in this case by activating GRB, SOS, SHC. Alternatively, a non RTK receptor, like TCR-LCK or BCR-Lyn, can activate RAS by a pathway involving calcium influx and DAG. The RAS-MAPK signaling pathway plays a particularly important role in proliferation. RAS GTPases are activated by many receptors, such as TCR, BCR, and CSF-1R, and recruit MAPK complexes. These complexes are formed by scaffolds, such as KSR, binding to the three-tier MAPK module that comprises RAF, MEK, and ERK. When activated by RAS (H-RAS, K-RAS, N-RAS), the MAPKKK RAF (RAF-1, A-RAF, B-RAF) phosphorylates the MAPKK MEK (MEK1, MEK2), which in turn phosphorylates the MAPK ERK (ERK1, ERK2). Activated ERK kinases phosphorylate the transcription factors MYC and AP-1 (JUN/FOS), leading to transcription activation of Cyclin D1, CDK4, and CDK6. Mono phosphorylation of retinoblastoma protein (RB) by Cyclin D-CDK4/6 is required for cells to leave quiescence and enter the cell cycle.
T-Cell Receptor
Activation of T cells occurs upon ligation of the T-cell receptor (TCR) by major histocompatibility complex (MHC) molecules in antigen presenting cells. The TCR and its coreceptors CD4 and CD8 have no intrinsic enzymatic activity. Instead, the associated non–RTK LCK (lymphocyte-specific protein tyrosine kinase) binds to cytoplasmic domains of TCR coreceptors CD4 and CD8, and their activation leads to phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in CD3. Phosphorylated CD3 recruits the tyro sine kinase zeta-chain-associated protein kinase 70 (ZAP70), leading to a cascade of phosphorylation events that in turn activates LAT (linker for activation of T cells) complexes. The LAT signalosome triggers the release of intracellular Ca2+ and the production of diacyl glycerol (DAG). The latter activates RAS-MAPK and protein kinase C (PKC)–nuclear factor κB (NF-κB) signaling pathways.
B-Cell Receptor
Every normal B cell has a unique B-cell receptor (BCR) consisting of pairs of immunoglobulin heavy (IgH) and light (IgL) chains. Each IgH and IgL has a unique variable region that allows the BCR to recognize and bind to diverse antigens, both soluble and on the sur face of antigen-presenting cells. Antigen-induced aggregation of BCR leads to phosphorylation of ITAMs by the Src family tyrosine kinase LYN. This phosphorylation event initiates the assembly of intracellular signaling molecules, including SYK, PLCγ2, Bruton tyrosine kinase (BTK), VAV, and the adaptor B-cell linker (BLNK). The BCR coreceptor CD19 is also phosphorylated by LYN, leading to the recruitment of PI3K, BTK, and AKT. Together, this signaling leads to the release of intracellular Ca2+ and production of DAG, and ultimately leads to activation of RAS-MAPK and PKC–NF-κB signaling pathways.
Macrophage Colony-Stimulating Factor Receptor
The known ligands of macrophage colony-stimulating factor 1 receptor (CSF-1R) are CSF-1 and interleukin (IL)-34. CSF-1 was the first hemopoietic growth factor to be isolated, and it can pro mote the growth of pure colonies of macrophages from bone marrow progenitors. CSF-1R is an RTK that belongs to the platelet-derived growth factor family. The binding of CSF-1 or IL-34 to CSF-1R leads to dimerization of CSF-1R, which allows autophosphorylation. Numerous proteins, such as GRB2, SOS, SFK, CBL, and p85, are recruited to the intracellular domain phosphotyrosines, leading to the activation of the PI3K-AKT and RAS-MAPK pathways, among others.
RAS Pathway to Cyclin D
The RAS-MAPK pathway is evolutionarily conserved and controls many fundamental processes, including cell proliferation. RAS guano sine triphosphatases (GTPases) are activated by many receptors, such as TCR, BCR, and CSF-1R, and recruit MAPK complexes. These complexes are formed by scaffolds, such as KSR (kinase suppressor of RAS), binding to the three-tier MAPK module that comprises RAF, mitogen-activated protein kinase (MEK), and extracellular signal regulated kinase (ERK). When activated by RAS (H-RAS, K-RAS, N-RAS), the MAPKKK RAF (RAF-1, A-RAF, B-RAF) phosphorylates the MAPKK MEK (MEK1, MEK2), which in turn phosphorylates the MAPK ERK (ERK1, ERK2). The principal function of RAS in cell cycle induction is to inactivate retinoblastoma protein (RB), relieving cells from its growth-inhibitory actions. The RAS MAPK signaling pathway is required to induce complexes of cyclin D1 and CDK4/CDK6. Activated ERK kinases phosphorylate the transcription factors MYC and activator protein 1 (AP-1), leading to transcription activation of cyclin D1, CDK4, and CDK6. Notably, PI3K-AKT and PKC–NF-κB pathways cooperate with RAS-MAPK in activating cyclin D1. Mono-phosphorylation of RB by cyclin D CDK4/6 is required for cells to leave quiescence and enter the cell cycle. Given the important functions of RAS-MAPK signaling in cell proliferation, it is not surprising that cancer hijacks this pathway: K-RAS, N-RAS, and B-RAF are frequently mutated in cancer, leading to constant activation of the RAS-MAPK pathway.
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