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SUMMARY:PTEN phosphatase-independent maintenance of apical membrane integr
 ity during colorectal glandular morphogenesis. - Professor F. C. Campbell 
 from the Centre for Cancer Research &amp\; Cell Biology\, Queen's Universi
 ty\, Belfast 
DTSTART:20121101T143000Z
DTEND:20121101T153000Z
UID:TALK40467@talks.cam.ac.uk
CONTACT:Caroline Newnham
DESCRIPTION:Evolutionarily conserved polarization and morphogenic pathways
  are critically important for human cancer outcomes. The tumour suppressor
  PTEN regulates the cdc42/PAR/aPKC polarity complex. PTEN  -  deficiency i
 s associated with impaired glandular morphogenesis that confers poor outlo
 ok in human colorectal cancer (CRC). We have investigated PTEN  -  depende
 nt glandular morphogenesis in a 3D organotypic Caco - 2 colorectal model s
 ystem. PTEN  -  mediated morphogenesis is dependent on coupling of cdc42 t
 o spatial cues at the apical membrane (AM). Parental Caco  -  2 cells form
 ed regular hollow gland  -  like structures (glands) with polarized epithe
 lial cells lined by a uniform AM interface around a single central lumen\,
  in 3D culture. PTEN knockdown influenced expression or localization of cd
 c42 guanine nucleotide exchange factors (GEFs)\, inhibited cdc42 activatio
 n\, disrupted AM integrity and induced a multilumen Caco  -  2 glandular p
 henotype evocative of high grade cancer. While PTEN has lipid phosphatase-
 dependent and  -  independent functions\, Caco  -  2 morphogenesis was una
 ffected by oncogenic phosphatidylinositol 3  -  kinase (PI3K) signalling o
 r PI3K - targeted treatment. To investigate effects of PTEN functional dom
 ains\, we assessed effects of catalytically-active or  -  inactive PTEN mu
 tants on cdc42 activity and/or AM integrity during 3D Caco  -  2 morphogen
 esis. Here we show that PTEN mutants containing an intact C2 domain enhanc
 ed cdc42 activity in PTEN  -  deficient colorectal epithelium. Transfectio
 n of PTEN  -  deficient Caco  -  2 (Caco  -  2 ShPTEN) cultures with the P
 TEN C2 domain rescued AM integrity and defective 3D morphogenesis. Convers
 ely\, a C2 domain construct mutated at its CBR3 lipid-binding motif was in
 effective. Fundamental attributes of the model system viz associations bet
 ween AM integrity and gland morphology were conserved and had prognostic s
 ignificance in human CRC. Taken together\, these data show PTEN influences
  AM dynamics and gland formation in a predictive CRC morphogenesis model s
 ystem\, substantively through its catalytically inert membrane-targeting C
 2 domain. Dissection of PTEN C2-cdc42 regulatory pathways of AM integrity 
 may identify molecular targets for novel therapy\, aimed at high grade CRC
 .  
LOCATION:Part II Room\, Department of Genetics
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