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The 14-3-3 family proteins exert their functions by interacting with their target proteins. In the intestine cells, 14-3-3 family proteins participate many critical signaling cascades governing cell differentiation, survival, apoptosis and polarity. The expression levels of 14-3-3 family proteins were mis-regulated in most colorectal cancers, and thus they may serve as progonostic biomarker for colorectal cancers. The 14-3-3 proteins may also have roles in protecting intestine cells from radiation exposure and parasites infection. Overall, the 14-3-3 family proteins play multiple roles in intestine and are critical in maintaining intestine health.