thrombopoietin-mediated signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by thrombopoietin binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. [GOC:nhn, GOC:signaling, PMID:19630807]

Thrombopoietin (TPO), a cytokine primarily produced by the liver, plays a pivotal role in regulating megakaryopoiesis, the process of platelet production. TPO exerts its effects by binding to its cognate receptor, the thrombopoietin receptor (c-mpl), expressed on the surface of megakaryocyte progenitors and mature megakaryocytes. Upon TPO binding, c-mpl undergoes dimerization and activation of its intrinsic tyrosine kinase activity. This initiates a cascade of intracellular signaling events that ultimately lead to megakaryocyte proliferation, differentiation, and platelet formation.

The TPO-mediated signaling pathway involves the following key steps:

1. **Ligand Binding and Receptor Dimerization:** TPO binds to the extracellular domain of c-mpl, causing receptor dimerization.

2. **Tyrosine Kinase Activation:** Dimerization activates the intrinsic tyrosine kinase activity of c-mpl, leading to autophosphorylation of tyrosine residues within the receptor's cytoplasmic tail.

3. **Recruitment of Signaling Adaptor Proteins:** Phosphorylated tyrosine residues on c-mpl serve as docking sites for various signaling adaptor proteins, including SH2 domain-containing proteins like Grb2 and Shc.

4. **Activation of the Ras/MAPK Pathway:** Grb2, upon binding to c-mpl, recruits the guanine nucleotide exchange factor SOS. SOS activates the Ras protein, a small GTPase. Activated Ras triggers a downstream signaling cascade involving the mitogen-activated protein kinase (MAPK) pathway, leading to increased transcription of genes involved in megakaryocyte proliferation and survival.

5. **Activation of the PI3K/Akt Pathway:** Shc, another adaptor protein recruited by c-mpl, activates the phosphatidylinositol 3-kinase (PI3K). PI3K phosphorylates phosphatidylinositol (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 activates the protein kinase B (Akt), a serine/threonine kinase that promotes cell survival and inhibits apoptosis.

6. **Activation of the JAK/STAT Pathway:** TPO binding to c-mpl also activates the Janus kinase (JAK) family of tyrosine kinases. JAKs phosphorylate c-mpl and themselves, creating docking sites for the signal transducer and activator of transcription (STAT) proteins. Activated STAT proteins translocate to the nucleus, where they bind to specific DNA sequences and regulate the expression of genes involved in megakaryocyte differentiation and platelet production.

7. **Regulation of Megakaryocyte Maturation and Platelet Formation:** The TPO signaling pathway ultimately orchestrates a complex interplay of transcription factors, signaling molecules, and downstream effectors that govern megakaryocyte differentiation, polyploidization, and platelet formation.

The TPO-mediated signaling pathway is tightly regulated to ensure appropriate platelet production. Levels of TPO in the blood are inversely proportional to the number of circulating platelets, providing a negative feedback loop to maintain platelet homeostasis. This regulatory mechanism ensures adequate platelet production without overproduction, which can lead to thrombotic events.'
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Proteins (1)

Compounds (4)