CD110 MPL(myeloproliferative leukemia virus oncogene),TPO-R (thrombopoietin receptor), C-MPL
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Lineage Restricted Molecule
Type 1 glycoprotein
Megakaryocyte
Platelet
Stem Cell
Progenitor Cell
Hematopoietic Cell
85 / 85
92 / 92

Expression
CD110 is expressed on hematopoietic stem and progenitor cells, megakaryocyte progenitors, megakaryocytes, and platelets.  CD110 is weakly expressed on CD34+ primitive cells. CD110 is the receptor for thrombopoietin and upon binding, megakaryocyte proliferation and differentiation is induced and stem cells are protected from apoptosis.  CD110 is located on the membrane.


Structure
MOLECULAR FAMILY NAME: Belongs to the hematopoietin receptor family.

CD110 is a single-chain type-1 635 aa glycoprotein.  It contains  a 25 aa signal sequence, a 466 aa extracellular domain which contains 2 fibronectin type-3 domains and has 4 potential N-linked glycosylation sites, a 22 aa transmembrane domain and an 122 aa intracellular cytoplasmic domain which contains 2 cytokine receptor box 1 motifs which are needed for ligand-induced proliferation and differentiation.  CD110 dimerizes upon binding of thromopoietin enabling the intracellular binding of JAK2 to the box 1 motif which results in tyrosine phosphorylation.  The thrombopoietin receptor (TPOR) was originally defined as the cellular counterpart of the myeloproliferative leukemia (MPL) virus oncogene capable of immortalizing bone marrow hematopoietic cells from different lineages.  The human homologue was cloned c-mpl which encoded a protein that was homologous with the TPOR superfamily and belongs to the cytokine receptor superfamily and therefore is part of the Ig superfamily.  The ligand for c-mpl, TPO, was cloned and shown to be the major regulator of megakaryocytopoiesis and platelet formation.  The CD110 gene consists of 12 exons. Exon 1 encodes a signal peptide, exons 2-9 encode the extracellular domain, exon 10 encodes the transmembrane domain, and exons 11-12 encode the intracellular domain.  CD110 has no intrinsic tyrosine kinase activity.

MOLECULAR MASS
Cell Type Unreduced Reduced
Platelets 85-92 kDa
Dami 82-84 kDa
BaF3/murine MPL 95 kDa
HEL 70 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.  CD110 mDNA comprises 4 different forms. MPL-P encodes the full-length protein.  MPL-K differs from MPL-P in the cytoplasmic domain in that the 1st half of intron 10, and exon 11 and 12 are missing in the cytoplasmic domain of MPL-K.  MPL-S encodes a potentially soluble form of CD110 that lacks exons 9 and 10.  MPL-del encodes an inactive splice variant that lacks 24 aa in the extracellular domain exon 9.

POST-TRANSLATIONAL MODIFICATION

CD110's extracellular domain contains 4 potential sites for asparagine-linked glycosylation with 117 aa, 178 aa, 298 aa, and 358 aa.  The intracellular domain contains 5 tyrosine residues with 512 aa, 542 aa, 591 aa, 626 aa, and 631 aa.  Upon binding of thrombopoietin, CD110 becomes phosphorylated.


Ligands
Thrombopoietin was revealed as a ligand by virtue of its stimulatory activity on a cell line expressing thrombopoietin receptor.

LIGANDS AND MOLECULES ASSOCIATED WITH CD110
Molecule Comment
Thrombopoietin The cytokine thrombopoietin binds to CD110, thereby inducing megakaryocyte growth and differentiation
JAK2 Binds to box 1 motif in intracellular domain after receptor dimerization induced by binding of thrombopoietin.  Upon JAK2 binding CD110 is tyrosine phosphorylated


Function
CD110 is the main regulator of megakaryocyte and platelet formation.  The CD110 binding results in the prevention of apoptosis, stimulation of cell growth and differentiation, and clearance of the ligand from the circulation.   Mice lacking the CD110 are deficient in megakaryocytes and their precursors.  Knockout mice, approximately 10%-20% of wildtype mice have severely decreased numbers of megakaryocytes and platelets as well as diminished counts of all other hematopoietic progenitors but normal hemoglobulin, leukocyte counts and white blood cell counts.  Mutations of CD110 such as the introduction of cysteines into the predicted dimer interface result in an activated, ligand-independent phenotype with functional consequences similar to those observed in the myeloproliferative disease induced by v-mpl in mice.  Upon binding of TPO to TPOR, the JAK family of non-receptor tyrosine kinases, the STAT family, the MARK family, the adaptor protein Shc and the receptors, activates the signal transduction pathway and becomes tyrosine phosphorylated.

BIOCHEMICAL ACTIVITY

CD110 is a receptor for thrombopoietin (TPO).

DISEASE RELEVANCE AND FUNCTION OF CD110 IN INTACT ANIMAL: 

Mutations in CD110 are found in some patients with congenital amegakaryocytic thrombocytopenia, a disease characterized by severe congenital thrombocytopenia with variable bleeding tendency and absence of megakaryocytes in the bone marrow.




Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD110: No information.

SUBSTRATES

CD110 is a substrate that is phosphorylated.

ENZYMES WHICH MODIFY CD110: No information.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 4352P40238
MouseS35317G08351Z22649
Antibodies

Revised June 25, 2008


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