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Bruton s tyrosine kinase (Btk) is a member of the Tee family of tyrosine kinases and mutations affecting Btk cause immunodeficiency in both humans and mice.Here,we show that in the presence of proteasome-specific inhibitors and/or phorbol esters,steady-state levels of Btk protein are reduced due to decreased transcription.Posttranslational modification of Btk by means of ubiquitination was observed,the degree of which was related to the level of expression and activation.The E3 ubiquitin ligase Cbl,which binds to Btk,was also found to ubiquitinate this kinase.In cells expressing high levels of Btk,accumulation of Btk was observed in a distinct microtubule dependent perinuclear compartment,the aggresome.Collectively this shows that the fate of the Btk protein is dictated by its expression level through the ubiquitin pathway.