TRIB3 Pseudokinase Is Induced Via An EPO/EPOR/STAT5 Pathway, Markedly up-Modulated in Late-Stage Erythroblasts, and Plays An Essential Non-Redundant Role During Stress Erythropoiesis.

Abstract 1985

Poster Board I-1007

TRIB pseudokinases have been implicated as pro-leukemogenic factors, and candidate regulators of insulin-dependent glucose utilization, adipogenesis and obesity. In a hematopoietic context, we have discovered that TRIB3 is a major new EPOR/JAK2/STAT5 response factor which furthermore is selectively elevated (among TRIB-1, -2 and -3) ≥ 10 fold in late-stage murine and human erythroblasts. We therefore have hypothesized that TRIB3 may selectively affect stress erythropoiesis, and have critically addressed this problem by generating novel TRIB3^flox/flox and TRIB3-null mice. At steady state, hematopoiesis among TRIB3-null mice is largely unperturbed. When challenged with hemolytic anemia, however, TRIB3- deficient mice exhibit worsened anemia (increased severity, and recovery time). Analyses of possible stage-specific effects further indicate faltered erythropoiesis at relatively late Kit^neg CD71^high Ter119^pos erythroblast stage. Recently, TRIBs have been revealed to act as apparent E3 ubiquitin ligase coupling factors. It is therefore intriguing to speculate that TRIB3 may act selectively during stress erythropoiesis to target and decay a key late-stage negative regulator.