As loss of PTEN tumor suppressive function resulting in aberrant Akt activation is a prevalent event in human cancers and associated with cancer metastasis, it is important to identify the key effector downstream of the PTEN/PI3K/Akt pathway that drives cancer progression and metastasis. Using the biochemical approaches and mouse genetic models, we identified Skp2 as an important Akt substrate that plays a critical for PTEN/Akt-mediated tumorigenesis. Skp2 (S-phase kinase associated protein-2), an F-box protein, is an E3 ligase component of Skp2 SCF complex responsible for substrate recognition. Skp2 overexpression induces cell cycle entry, and the degradation of p27 is responsible for Skp2-mediated cell cycle progression. Although Skp2 is overexpressed in numerous human cancers and associates with cancer metastasis 1,2, it remains unclear how Skp2 overexpression occurs during cancer progression and how its oncogenic activity is regulated. Our study provides for the first time that Akt kinase phosphorylates Skp2 at S72 and Skp2 S72 phosphorylation is a molecular switch that orchestrates Skp2 E3 ligase activity and oncogenic functions. The objective of this application is to determine the functional crosstalk between PTEN/PI3K/Akt signal and Skp2 S72 phosphorylation in prostate cancer progression and metastasis. The Central hypothesis of the application is that Skp2 S72 phosphorylation by PI3K/Akt is critical for prostate cancer progression and metastasis. Our Central hypothesis has been formulated on the basis of our strong preliminary data. The rationale of the proposed research is that, once the important role of Skp2 S72 phosphorylation is confirmed and established in prostate cancer progression and metastasis, the better treatment or target for prostate cancer can be achieved. We plan to test our Central hypothesis and accomplish the objective of this application by pursuing the following specific aims: Aim 1) To determine the molecular mechanism by which Skp2 gene expression and activity are regulated by the PI3K/Akt pathway. Aim 2) To determine the potential role of Skp2 S72 phosphorylation in prostate cancer progression. Aim 3) To determine the functional crosstalk between Akt and Skp2 in cell migration and invasion. Aim 4) To determine the potential role of Skp2 and Skp2 S72 phosphorylation in prostate cancer metastasis. This proposal work is innovative, because it provides for the first time that Akt is a kinase for Skp2 and that Skp2 S72 phosphorylation by Akt is critical for Skp2 E3 ligase activity, cytosolic localization, and oncogenic functions. Importantly, our study reveals that Skp2 is a critical downstream effector for the PTEN/PI3K/Akt signal in animal models of prostate cancers. With respected outcomes, the combination of work in this proposal is collectively expected to uncover the critical role Skp2 S72 phosphorylation in prostate cancer progression and metastasis. Such results will have an important positive impact and may therefore provide a potentially therapeutic target for prostate cancer treatment. Our results will also fundamentally advance our current understandings of how prostate cancer develops and further progresses into the metastasis stage.