Model for assembly and activation of hβ_c mutants FIΔ and V449E. The high-affinity complex of the GM-CSF receptor (GMR) is a dodecamer structure (center) comprising 2 ligand bound hexamers.¹²  The central structure in the dodecamer complex enables JAK2 transphosphorylation and activation of STAT5- and Shc-mediated pathways. Proposed signaling through GMR-α occurs in αβ heterodimers (outer structures in the dodecamer complex), which initiate activation of Akt and NFκB pathways. Also indicated is a possible negative feedback mechanism whereby activation of SHIP downstream of JAK2 may suppress Akt activation. The proposed V449E structure is represented as a β_c tetramer, which does not require GMR-α and initiates a subset of the signals generated by the dodecameric GMR complex. V449E-activated pathways are confined to those downstream of JAK2 and receptor tyrosine phosphorylation and support survival and proliferation in the FDB1 cells. The proposed FIΔ structure comprises an αβ tetramer that precludes JAK2 transphosphorylation. This complex generates signals predominantly through GMR-α and results in activation of Akt and NFκB pathways, supporting FDB1 survival and differentiation.