[Keywords: YAP; Lats; Mst; contact inhibition; NF2; Hippo] Supplemental material is available at http://www.genesdev.org.

[Keywords: TEAD; YAP; CTGF; Hippo; transcription, cancer] Supplemental material is available at http://www.genesdev.org.

The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germline mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that female mice heterozygous for the "scurfin" mutation of the Foxp3 gene (Foxp3(sf/+)) developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and HER-2/ErbB2 was overexpressed. Foxp3 bound and repressed the HER-2/ErbB2 promoter. Deletion, functionally significant somatic mutations, and downregulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2/ErbB2 overexpression, regardless of the status of HER-2 amplification. Our data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.

Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene residing at Xp11.23 in human prostate cancer. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly over-expressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is an X-linked prostate tumor suppressor in the male. Since the male has only one X chromosome, our data represents a paradigm of “single-genetic-hit” inactivation-mediated carcinogenesis.

The axon guidance cue netrin is importantly involved in neuronal development. DCC (deleted in colorectal cancer) is a functional receptor for netrin and mediates axon outgrowth and the steering response. Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.During embryonic development, neurons are guided to specific targets by extracellular cues in their environment. Axon growth cones sense various chemoattractive and chemorepulsive signals and translate these signals, via intracellular signal transduction pathways, into cellular movements that ultimately steer them to their correct targets. Several axon guidance molecules have been discovered and characterized, including a soluble family of proteins called netrins 1-3 . Netrins can stimulate axon growth in addition to eliciting both attractive and repulsive responses 4 .Correspondence should be addressed to K.-L.G. (kunliang@umich.edu). Competing Interests Statement:The authors declare that they have no competing financial interests.Note: Supplementary information is available on the Nature Neuroscience website. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2008 May 6. Published in final edited form as:Nat Neurosci. 2004 November ; 7(11): 1213-1221. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGenetic studies in Caenorhabditis elegans indicate that UNC-40 and UNC-5 are functional receptors for UNC-6, a netrin homolog 5-7 . The mammalian homolog of UNC-40 is DCC, originally identified as a tumor suppressor gene 8 . DCC mediates both the axon growth and the chemoattractive function of netrin 6,7,9 . In addition, DCC mediates growth cone repulsion when in a complex with the UNC-5 receptor 5,10-13 . The UNC-40 and UNC-5 receptor complex is required for the dorsoventral repulsion of both neurons and gonads in C. elegans. The biological functions of netrin and its receptors in axon growth and growth cone guidance have been well studied; the intracellular signal transduction pathways downstream of the netrin receptors, however, are only partially understood.Tyrosine phosphorylation may be involved downstream of guidance receptors, as phosphorylation of both DCC and UNC-5 has been observed 14 . Furthermore, coexpression of Src, a tyrosine kinase, increases UNC-5 tyrosine phosphorylation, indicating a Results Netrin stimulates tyrosine phosphorylation of DCC and FAKIt has b...