[6] Of these cytokines it most closely resembles leukemia inhibitory factor (LIF) in both structure and function.
A partial amino acid sequence allowed the isolation of human OSM cDNA and subsequently genomic clones.
[12] Thus, post translational processing may play a significant role in the in vivo function of OSM.
Like many cytokines OSM is produced from cells by de novo synthesis followed by release through the classical secretion pathway.
[15] These data suggest that OSM and LIF arose relatively recently in evolutionary terms by gene duplication.
The three-dimensional structure of human OSM has been solved to atomic resolution, confirming the predicted long chain four helix bundle topology.
A distinctive kink in the A helix arises from departure of the classical alpha helical H-bonding pattern, a feature shared with all known structures of LIFR using cytokines.
Scatchard analysis of radio ligand binding data from 125I-OSM binding to a variety of OSM responsive cell lines produced curvilinear graphs which the authors interpreted as the presence of two receptor species, a high affinity form with an approximate dissociation constant Kd of 1-10 pM, and a low affinity form of 0.4-1 nM.
[18] This data hinted to the existence of an additional ligand specific receptor chain which led to the cloning of OSMR.
The nomenclature of these sites is taken by direct analogy to Growth Hormone, probably the best studied of four helix bundle cytokines.
Cytokines that recruit LIFR via site 3 i.e. LIF, OSM, CNTF and CT-1 possess these conserved phenylalanine and lysine residues and is known as the FK motif.
These differences in signaling character, in addition to the tissue distribution profiles of OSMRb and LIFRb, offer another variable in the distinction between the common and specific cellular effects of OSM with respect to LIF.
[8][23] JAK1, JAK2, and tyk2 are not interchangeable in the gp130 system, this has been demonstrated with the use of JAK1, Jak2 or Tyk2 deficient cell lines obtained from mutant mice.
In addition these receptors also contain a serine rich region and a third more poorly conserved motif termed box 3.
Gp130 contains box1 and box2 sequences within the membrane-proximal part of the cytoplasmic region, lying within the minimum 61 amino acids required for receptor activation.
Studies with various gp130 truncation mutants show a reduction of Jak2 binding and abrogation of certain biological effects upon deletion of box2.
The first 65 amino acid residues in the cytoplasmic domain of LIFR, in combination with full length gp130, can generate signalling on treatment with LIF.
It is important to note that before 1997[38] differences in human and murine OSM receptor usage were unknown.
[39] Stimulation of a primary endothelial culture (HUVEC) with hOSM results in delayed but prolonged upregulation of P-selectin,[40] which facilitates leukocyte adhesion and rolling, necessary for their extravasation.
For example, OSM reduces the degree of joint destruction in an antibody induced model of rheumatoid arthritis.
[41] OSM is a major growth factor for Kaposi's sarcoma "spindle cells", which are of endothelial origin.