Numb serves as a key regulator of Notch and Sonic Hedgehog signaling and also modulates p53 protein levels. Numblike is a highly conserved homolog to mammalian Numb, but considerably less is known about its function. To address the role of Numblike, we have generated a mouse embryonic stem (ES) cell line, Nbl(TetOn), in which expression of Numblike can be induced and analyzed the effect of activation of Numblike. Induction of Numblike, similar to Numb, reduced the amount of Notch receptor, whereas Numblike differed from Numb with regard to p53 and Shh signaling. In contrast to Numb, Numblike did not elevate the level of p53 protein and Numblike potentiated, rather than reduced, the immediate downstream response of Shh signaling. In keeping with a role for Numblike in potentiating Shh signaling, Shh and Numblike synergistically increased the proportion of ES cells expressing pluripotency markers. In conclusion, the data demonstrate that Numb and Numblike have evolved to acquire at least partially distinct functions.
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