[PDF][PDF] Linking colorectal cancer to Wnt signaling

M Bienz, H Clevers - Cell, 2000 - cell.com
Cell, 2000cell.com
Tumors of the colorectum are amongst the most comof the new discoveries that are relevant
to colorectal mon human neoplasms. Approximately 5% of the Westcancer in humans have
emerged from genetic and cellern population will develop colorectal malignancies
durbiological studies in animal model systems. ing their lifetime. A small fraction of these
occur in an apparently inherited fashion. One of the best defined The Canonical Wnt
Pathway though rare forms of such cancer syndromes is familial Combined work in flies …
Tumors of the colorectum are amongst the most comof the new discoveries that are relevant to colorectal mon human neoplasms. Approximately 5% of the Westcancer in humans have emerged from genetic and cellern population will develop colorectal malignancies durbiological studies in animal model systems. ing their lifetime. A small fraction of these occur in an apparently inherited fashion. One of the best defined The Canonical Wnt Pathway though rare forms of such cancer syndromes is familial Combined work in flies, frogs, and mammals produced adenomatous polyposis (FAP). Patients with FAP dethe main outline of the canonical Wnt/ß-catenin signalvelop large numbers of benign adenomatous polyps of ing pathway as we currently know it (Figure 1). This the colorectal epithelium in early adulthood. Almost inpathway plays a key role during normal animal developvariably, some of these will progress into invasiveness ment (Cadigan and Nusse, 1997). In the following, we and, ultimately, metastasize. With variable penetrance, shall attempt to sketch out the core issues regarding FAP patients will also develop neoplastic lesions at exthe transduction of the Wnt signal, focusing on aspects tracolonic sites, for example desmoids, ampullary carcithat are relevant to cancer. For more comprehensive nomas, and hepatoblastomas (Kinzler and Vogelstein, information on this pathway, the reader is referred to 1996; Lal and Gallinger, 2000). the Wnt homepage (http://www. stanford. edu/rnusse/In 1991, the tumor suppressor Adenomatous polypowntwindow. html). sis coli (APC) encoded by the FAP locus was identified In unstimulated cells, free cytoplasmic ß-catenin/Arby molecular cloning (Groden et al., 1991; Kinzler et al., madillo is destabilized by a multiprotein complex con-1991). It turned out that, not only the tumors from FAP taining Axin (or its homolog Conductin), glycogen synpatients, but also most sporadic colorectal tumors have thase kinase 3ß (GSK3, or Shaggy/Zeste-white 3 in both APC alleles inactivated (Nagase and Nakamura, Drosophila) and the APC tumor suppressor (Zeng et al., 1993). APC is a large protein whose sequence, at the 1997; Behrens et al., 1998; Hart et al., 1998; Fagotto et time, was uninformative. Physical interactions of APC al., 1999; Kishida et al., 1999a). Axin/Conductin has a with several cellular proteins were tentatively identified. scaffold function in this complex, binding to APC, GSK3, The discovery that APC binds to ß-catenin (Rubinfeld and ß-catenin/Armadillo. Interaction between Axin and et al., 1993; Su et al., 1993) provided the first significant GSK3 in the complex facilitates efficient phosphorylaclue as to the molecular function of APC, and identified tion of ß-catenin by GSK3 (Ikeda et al., 1998), most likely what is now thought to be its most critical molecular at critical serine and threonine residues in its N terminus target.(Aberle et al., 1997). This phosphorylation event ear-This discovery initially suggested a function of APC marks ß-catenin/Armadillo for ubiquitination by the SCF in cadherin-based cellular adhesion in which ß-catenin complex (containing the F box protein ßTrCP/Slimb) plays a critical role (eg, Hulsken et al., 1994; see below).(Jiang and Struhl, 1998; Marikawa and Elinson, 1998), and for subsequent degradation by the proteasome
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