Table 1. EPO/EPOR-modulated signal transduction factors.
gene symbol, name and Entrez ID | EPO modulation (fold change) array/RTPCR | known /novel EPO target | Description | references |
Pik3cb, phosphatidylinositol 3-kinase catalytic beta subunit [74769] | 2.6× up | N | p110beta catalytic subunit of PI3K | (18594509); (19815050) |
Mobkl1a, MOB1, Mps One Binder kinase activator-like 1A [68473] | 2.2× up | N | NDR kinase regulator | (20624913); (18328708) |
Prkcq, protein kinase C-theta [18761] | 2.3× up | N | PKC theta S/T kinase | (20592275); (12670396) |
Gnb2l1, G protein, beta polypeptide 2 like 1 [14694] | 3.0× up | N | G-protein beta 2-like-1 (anchor for PKC) | (19767770); (20093473) |
Gab2, growth factor receptor bound protein 2-associated protein 2 [14389] | 2.7× up | N | Grb2 and SHP2 docking protein | (14662016); (20161778); (17374739) |
Irs2, insulin receptor substrate 2 [384783] | 7.4× up | K | insulin and IL4PY- regulated docking protein | (19109238); (12506011) |
Erbb2ip, Erbb2 interacting protein [59079] | 3.1× down | N | Erbin, RTK and TGF-R modulator | (17591701); (20887249) |
Tirap, TIR domain-containing adaptor protein [117149] | 2.4× up | N | IL1 and Toll receptor adaptor | (12447442); (19898489) |
Gnl3, guanine nucleotide binding protein-like 3 (nucleolar) [30877] | 2.3× up | N | nuclear receptor negative co-regulator | (20703089); (17623774) |
Pnrc1, proline-rich nuclear receptor coactivator 1 [108767] | 2.3× up | N | nuclear receptor positive co-regulator | (10894149); (20023006) |
Nol8, nucleolar protein 8 [70930] | 3.1× up | N | GTP binding protein – binding protein | (15132771); (14660641) |
Plek2, plecstrin 2 [27260] | 3.9× up | N | Pleckstrin2, PIP-regulated cytoskeletal factor | (17658464); (17008542) |
Twelve additional signal transduction factors (STFs) were defined as significantly EPO/EPOR- modulated targets: two are kinases, as PI3K p110beta and PKC theta; others include Rack1/Gnb2l1, Erbin/Erbb2ip (an RTK modulator), two docking proteins (Gab2, Irs2), and Pleckstrin2. References are cited by PMID number.
Among twelve remaining EPO/EPOR modulated STF's (Table 1, including references as PMID's), one has been reported previously as insulin receptor substrate-2 (Irs2), a docking protein also utilized by the IL4R. Eleven represent novel EPO- response factors. One similarly is a docking protein, Gab2, while two are kinases as PI3K's catalytic beta subunit (Pik3cb), and PKC-theta (Prkcq) (an NFKb regulator). Another, MOB1 (Mobkl1a) is a preferred substrate of Mst1/2 Ste20- like kinases. Three are G- (or G-like) proteins (or binding proteins) as Gnb2l1, Gnl3 and Nol8; and three are regulating co-factors for RTKs, Toll receptors, and nuclear receptors as Erbin/Erbb2ip, Tirap, and Pnrc1, respectively. Finally, one EPO/EPOR response factor is a regulator of cytoskeleton restructuring as Pleckstrin-2 (Plek2) (3.9-fold induction). Thus, EPO also modulates the expression of intriguingly diverse sub-sets of novel STF's with functions that will be of significant interest to further delineate (and network).