ARM domain-dependent nuclear import of adenomatous polyposis coli protein is stimulated by the B56 alpha subunit of protein phosphatase 2A.
Inactivating mutations in the adenomatous polyposis coli (APC) gene correlate with progression of colon cancer and familial adenomatous polyposis. The APC tumor suppressor contributes to chromosome segregation and turnover of the oncogenic transcriptional activator beta-catenin, and these activities are impaired by truncating cancer mutations. APC was recently identified as a shuttling protein whose subcellular distribution is regulated by two nuclear localization signals (NLSs) and multiple nuclear export signals (NESs). Here, we show that mutant disease-linked truncated forms of APC, most of which lack the two central NLSs and certain NES sequences, retain nuclear-cytoplasmic shuttling activity. Nuclear export of truncated APC is mediated by a dominant N-terminal NES. Nuclear import of NLS-deficient APC mutants is facilitated by the N-terminal ARM domain. Furthermore, co-expression of the ARM-binding protein, B56 alpha, increased the nuclear localization of mutant and wild-type APC. The minimal B56 alpha-responsive sequence mapped to APC amino acids 302-625. B56 alpha is a regulatory subunit of protein phosphatase 2A; however, its ability to shift APC to the nucleus was independent of phosphatase activity. We conclude that APC nuclear import is regulated by the ARM domain through its interaction with B56 alpha and postulate that APC/B56 alpha complexes target the dephosphorylation of specific proteins within the nucleus.
Galea
M A
MA
Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, New South Wales 2145, Australia.
Eleftheriou
A
A
Henderson
B R
BR
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D054648:Protein Phosphatase 2; D021381:Protein Transport
D025601:Adenomatous Polyposis Coli Protein; D017931:DNA Primers; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2