Mechanism of activation of the TPO receptor by TPO. TPO binds the distal CRM (CRM 1) of the inactive TPO (c-Mpl) receptor and creates an activated receptor that initiates many downstream signal transduction events (see “First-generation thrombopoietic growth factors”). Although drawn as such here, the existence of preformed inactive dimers of the TPO receptor has not yet been convincingly demonstrated. Illustration by Paulette Dennis.