There presence in β2SP+/− mice and even following surgical resection suggests that β2SP plays a critical role in progenitor cell activation. Progenitor cells have only been described to become activated and proliferate in contexts in which hepatocyte proliferation is inhibited.3, 30 The mechanism underlying this reciprocal relationship, however, has yet to be elucidated. Evidence for the activation of hepatic progenitor cells is seen with our microarray analysis and immunostaining for β-catenin. Up-regulation of several Wnt-related genes and clear cytoplasmic and nuclear β-catenin expression suggest

an activated Wnt signaling pathway. Activated Wnt signaling has recently been shown to promote expansion of the progenitor cell population and occurs preferentially within the progenitor cell population.24, 31 Evidence that loss of β2SP not only expands hepatic Cytoskeletal Signaling inhibitor progenitor cells, but also results in a check details delayed mitogenic response of hepatocytes, suggests that β2SP may also play a critical and non-TGF-β-mediated role in the hepatocyte-progenitor cell interaction. Although inactivation of TGF-β signaling via the type II receptor resulted in an accelerated mitogenic response in conditional knockout mice, loss of β2SP results in an opposite effect. There is no evidence, however, of

accelerated apoptosis or significant loss of hepatocyte function, as all mutant mice survived with no significantly discernable morbidity. In fact, hepatocyte proliferation was merely delayed and rapidly corrected in β2SP+/− mice, as there was no evidence of a significant difference in liver mass: body weight ratio 1 week posthepatectomy. Therefore, it

is likely that reduced β2SP disrupts the health and proliferative capacity of hepatocytes following acute liver injury, thereby initiating activation of a progenitor cell compartment tasked with aiding the regeneration process (Fig. 5). The lack of complete β2SP loss, however, affords sufficient reserves to allow hepatocyte proliferation to proceed following a delay and allowing for the differentiation of activated progenitor cells to mature hepatocytes as regeneration terminates. An important implication of this work is demonstration of the key functional roles of TGF-β signaling Masitinib (AB1010) and, specifically, β2SP as a mediator of cell proliferation and differentiation. β2SP is a key TGF-β adaptor protein and possesses tumor suppressor function, particularly in HCC. It is clear from the present study, however, that β2SP regulation of liver proliferation, differentiation, and ultimately tumorigenesis is not so straightforward. There is substantial presumptive evidence suggesting that loss of β2SP may promote hepatic progenitor cell activation. This progenitor cell population, on repeated activation following repeated injury, may be more prone to malignant transformation and subsequent tumorigenesis.