SerpinB2, originally described as plasminogen activator inhibitor type 2 (PAI-2), is expressed by a range of cell types including activated macrophages and many tumors and is a major product of differentiating squamous epithelial cells (33, 43). PAI-2 was one of the first identified members of a unique and growing subclass of serine protease inhibitors (serpins) called ovalbumin-like serpins (ov-serpins) (49). Ov-serpin family members often appear to have nucleocytoplasmic distributions (8, 15), and many have intracellular activities: for instance, CrmA and PI9 are involved in apoptosis inhibition, MENT is involved in DNA binding, and Maspin and Headapin are involved in tumor suppression (8, 49). Although extracellular PAI-2 is well documented as an inhibitor of the extracellular protease urokinase-type plasminogen activator (31), PAI-2 was recently shown to have an additional intracellular activity as a retinoblastoma protein (Rb) binding protein (15). PAI-2 was found to bind the C pocket of Rb via a novel binding motif called the PENF homology motif, which is present in the large C-D interhelical loop region of PAI-2. PAI-2 expression resulted in decreased Rb turnover, with the subsequent increase in Rb levels causing an increase in Rb-mediated activities. The PAI-2-mediated increase in Rb protein levels required both Rb binding via the C-D interhelical region of PAI-2 and an intact reactive site loop (RSL), which plays a pivotal role in the known protease inhibitory activity of PAI-2 (15). The new Rb-associated role for intracellular PAI-2 may explain why PAI-2 expression is often able to confer a series of Rb-related phenotypes such as resistance to apoptosis (19,23,61), regulation of gene transcription (1, 37, 48), promotion of differentiation (29,34,57), and tumor suppression (20,23,31,34,38,41,56).A dramatic phenotype resulting from stable PAI-2 expression in HeLa cells was recovery of Rb and loss of E7 protein levels in these human papillomavirus type 18 (HPV-18)-transformed cells (15). High-risk HPVs such as HPV-18 are often associated with cervical cancer (16), and cells from such cancers usually constitutively express the HPV oncoproteins E6 and E7 from HPV-derived DNA integrated into the host cell genome (36). E6 targets p53 and c-Myc, and E7