The myelin-associated inhibitors (MAIs) Nogo-A and myelin-associated glycoprotein (MAG) are potent inhibitors of regeneration in the central nervous system (CNS). They effect inhibition through signaling pathways initiated by activation of the Nogo-66 receptor 1 (NgR1) complex, low-density lipoprotein (LDL) receptor-related protein-1 (LRP1), or paired immunoglobulin-like receptor B (PirB). The Smad2 protein, which is phosphorylated in response to transforming growth factor-β (TGFβ) receptor activation, has been shown to have a role in myelin-mediated inhibition of neurite outgrowth in cerebellar granule neurons (CGNs). We demonstrate that MAG and Nogo strongly induce Smad2 phosphorylation and that inhibiting TGFβ receptor activation abolishes this response in CGNs treated with MAG or Nogo. We have hypothesized that this receptor is being transactivated by another receptor such as NgR1, LRP1, or PirB. siRNA knockdown of NgR1 or LRP1 in CGNs did not result in significant reduction of Smad2 phosphorylation in response to MAG or Nogo. Similarly, CGNs from PirB-/- mice displayed no significant reduction in levels of phosphorylated Smad2 following treatment with MAG or Nogo. TGFβ receptor activation by MAIs is thus mediated through an unidentified receptor, and discovering this receptor may provide a novel target for pharmacological intervention as a means of promoting regeneration in the CNS following injury.