Casein kinase I (CKI) and GSK-3 phosphorylate -catenin at Ser 45 (-cat^45|) and Thr 41/Ser 37,33 (-cat^33,37,41) residues thereby facilitating its ubiquitination and proteasomal degradation. We utilized Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model to determine Ser/Thr phosphorylation and biological function of -catenin during crypt hyperproliferation. TMCH was associated with 3-fold and 3.3-fold increases in CKI cellular abundance and 2-fold and 1.8-fold increase in its activity after 6 and 12 day's post-infection, respectively. -Catenin co-immunoprecipitated with both cellular and nuclear CKI and cellular axin at these time points. Cellular -catenin was constitutively phosphorylated at Ser⁴⁵ and underwent sub-cellular redistribution to cytoskeletal and nuclear fractions at days 6 and 12 TMCH, respectively. -Cat^33,37,41, however, exhibited only subtle changes in either phosphorylation status or sub-cellular distribution even after blocking proteasomal degradation in vivo. GSK-3 underwent increased phosphorylation at Ser⁹ leading to 40% and 70% decreases in its activity at these time points. Co-ip studies exhibited strong association of GSK-3 with PKC at either time point. Cellular -cat⁴⁵ stabilized and alongwith unphosphorylated -catenin, underwent nuclear translocation and associated with nuclear accumulated Tcf-4 and CREB binding protein, CBP and was significantly acetylated leading to increases in DNA binding. Priming of -catenin at Ser⁴⁵ exists in vivo. However, -cat⁴⁵ does not necessarily enter the degradation pathway. Impairment in linking -cat⁴⁵ to subsequent GSK-3-mediated phosphorylation and degradation may account for increased steady state levels of both unphosphorylated as well as Ser⁴⁵-phosphorylated -catenin which may be causally linked to increases in cell census during TMCH.