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Gene Review

PDZD2  -  PDZ domain containing 2

Homo sapiens

Synonyms: AIPC, Activated in prostate cancer protein, KIAA0300, PAPIN, PDZ domain-containing protein 2, ...
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Disease relevance of PDZD2

  • Consistent with the beta-cell-enriched expression of PDZD2, immunoblot analysis indicated expression of both full-length PDZD2 and sPDZD2 in the insulinoma cell line INS-1E [1].
  • The data suggest that endogenous sPDZD2, produced by caspase-3-mediated cleavage from PDZD2, may function as a novel autocrine growth suppressor for human prostate cancer cells [2].
  • Immunohistochemical analysis of a tissue microarray comprising 158 tumor, 18 high-grade prostatic intraepithelial neoplasia, and 91 normal prostate specimens with an anti-AIPC antibody demonstrated abundant AIPC protein expression in 75% of tumors, 83% of prostatic intraepithelial neoplasia lesions, and 3% of normal tissues (P < 0.0001) [3].
  • PATIENTS AND METHODS: Twenty-eight men with AIPC and bone metastases were enrolled to receive imatinib 600 mg daily lead-in for 30 days, then imatinib 600 mg daily and one of six possible doses of docetaxel weekly for 4 weeks every 6 weeks [4].
  • The phospho-Ser/Thr-Pro specific prolyl-isomerase PIN1 is over-expressed in more than 50% of hepatocellular carcinomas (HCCs) [5].

Psychiatry related information on PDZD2

  • Pin1 has been shown to be essential for cell-cycle progression and to interact with the neuronal tau protein inhibiting its aggregation into fibrillar tangles as found in Alzheimer's disease [6].
  • Median response times with HDK tend to be brief but a significant minority of AIPC patients benefit with extended responses [7].

High impact information on PDZD2

  • A major clinical problem is the development of androgen-independent prostate cancer (AIPC) during antihormonal treatment [8].
  • Based on genetic data showing amplification of the c-myc gene in AIPC, we studied the ability of c-myc to confer AIPC cell growth [8].
  • Moreover, RNA interference directed against c-myc showed that growth of human AIPC cells, AR-positive or -negative, required c-myc expression [8].
  • We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC [9].
  • The role of imatinib in modulating outcomes to docetaxel in AIPC is being tested in a randomized phase II trial [4].

Chemical compound and disease context of PDZD2

  • PURPOSE: Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC) [9].
  • PURPOSE: To determine the safety and efficacy of weekly high-dose oral calcitriol (Rocaltrol, Roche Pharmaceuticals, Basel, Switzerland) and docetaxel (Taxotere, Aventis Pharmaceuticals, Bridgewater, NJ) in patients with metastatic androgen-independent prostate cancer (AIPC) [10].
  • PURPOSE: To evaluate the herbal combination, PC-SPES, and diethylstilbestrol (DES) in patients with androgen independent prostate cancer (AIPC) [11].
  • PURPOSE: To study the platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate in androgen-independent prostate cancer (AIPC), alone and in combination with docetaxel, we designed a modular phase I trial [4].
  • In total, 106 symptomatic AIPC patients were identified in whom prostatic biopsies (adenocarcinoma) were available both before the start of androgen deprivation (PRTR biopsy) and after the development of AIPC (AIPC biopsy) [12].

Biological context of PDZD2

  • Moreover, cells displaying Tau phosphorylation at Thr231 did not show any Pin1 nuclear depletion [13].
  • We isolated an extensive collection of functional mutant Pin1 clones harboring a total of 356 amino acid substitutions [14].
  • We have characterized the backbone dynamics of the peptidylprolyl isomerase (Pin1) catalytic domain in the free state and during catalysis [6].
  • Among abnormal Tau phosphorylation sites, pThr231 is of particular interest since it is associated with early stages of Alzheimer's disease and is a binding site of Pin1, a peptidyl-prolyl cis/trans isomerase mainly involved in cell cycle regulation [13].
  • Because of the diverse functions of Pin1, and the discovery that this protein is one of the oxidized proteins common to both MCI and AD brain, the question arises as to whether Pin1 is one of the driving forces for the initiation or progression of AD pathogenesis, finally leading to neurodegeneration and neuronal apoptosis [15].

Anatomical context of PDZD2

  • We have shown that PDZD2, which shows extensive homology to pro-interleukin-16 (pro-IL-16), is localized mainly to the endoplasmic reticulum (ER) [16].
  • To understand the possible functional role of PDZD2 in pancreas, we investigated the cellular distribution of PDZD2 in adult pancreas using an antiserum that recognizes both the full-length and secreted forms of PDZD2 [1].
  • Immunohistochemical analysis revealed a strong expression of PDZD2 in pancreatic islet beta cells but not alpha cells [1].
  • PAPIN and p0071 are ubiquitously expressed in various tissues and are localized at cell-cell junctions in normal rat kidney cells and bronchial epithelial cells [17].
  • Using RNA expression profiling techniques, we have identified a transcript originating from the activated in prostate cancer (AIPC) gene, the expression of which is preferentially up-regulated in several cultured prostate tumor cell lines and human primary prostate tumors [3].

Associations of PDZD2 with chemical compounds

  • CONCLUSION: The combination of weekly oral high-dose calcitriol and weekly docetaxel is a well-tolerated regimen for AIPC [10].
  • Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1 [18].
  • There was a parallel rise in the BSI and the PSA in 24 patients (105 scans) treated for AIPC with hydrocortisone followed by suramin at PSA relapse (Pearson's moment correlation, 0.71) [19].
  • Low concentrations of papin rapidly cleave solubilized or membrane-bound acetylcholine receptor (AcChR) from Torpedo californica into a wide range of small fragments [20].
  • The diazo compound, 2,2'-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPC), is a water-soluble radical initiator that can be activated at mild temperatures (37 degrees -40 degrees C) [21].

Physical interactions of PDZD2

  • PAPIN has six PDZ domains and interacts with p0071, a catenin-related protein [22].

Co-localisations of PDZD2

  • Furthermore, ERBIN and ErbB2 were colocalized with PAPIN on the lateral membrane [22].

Other interactions of PDZD2

  • The screen identified three specific PDZ domains that exhibit interactions with GABA(B)R2: Mupp1 PDZ13, PAPIN PDZ1, and Erbin PDZ [23].
  • We have examined whether the localization of PAPIN is determined by p0071 in epithelial cells [22].

Analytical, diagnostic and therapeutic context of PDZD2

  • Indeed, western blotting and mass spectrometry analysis of conditioned medium from cells transfected with epitope-tagged PDZD2 show that there is secretion of a PDZD2 peptide of approximately 37 kDa (sPDZD2, for secreted PDZD2) that contains two PDZ domains [16].
  • Sequence analysis revealed that the AIPC protein encodes six PDZ domains, which are protein-protein binding domains likely involved in protein clustering and scaffolding [3].
  • Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting [24].
  • Intermittent chemotherapy for AIPC is feasible and deserves further study [25].
  • CONCLUSIONS: There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC [26].


  1. Secreted PDZD2 exerts concentration-dependent effects on the proliferation of INS-1E cells. Ma, R.Y., Tam, T.S., Suen, A.P., Yeung, P.M., Tsang, S.W., Chung, S.K., Thomas, M.K., Leung, P.S., Yao, K.M. Int. J. Biochem. Cell Biol. (2006) [Pubmed]
  2. Inhibition of prostate cancer cell growth by human secreted PDZ domain-containing protein 2, a potential autocrine prostate tumor suppressor. Tam, C.W., Cheng, A.S., Ma, R.Y., Yao, K.M., Shiu, S.Y. Endocrinology (2006) [Pubmed]
  3. Activated in prostate cancer: a PDZ domain-containing protein highly expressed in human primary prostate tumors. Chaib, H., Rubin, M.A., Mucci, N.R., Li, L., Taylor JMG, n.u.l.l., Day, M.L., Rhim, J.S., Macoska, J.A. Cancer Res. (2001) [Pubmed]
  4. Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: a modular phase I trial in androgen-independent prostate cancer. Mathew, P., Thall, P.F., Jones, D., Perez, C., Bucana, C., Troncoso, P., Kim, S.J., Fidler, I.J., Logothetis, C. J. Clin. Oncol. (2004) [Pubmed]
  5. PIN1 expression contributes to hepatic carcinogenesis. Pang, R.W., Lee, T.K., Man, K., Poon, R.T., Fan, S.T., Kwong, Y.L., Tse, E. J. Pathol. (2006) [Pubmed]
  6. Structure and dynamics of pin1 during catalysis by NMR. Labeikovsky, W., Eisenmesser, E.Z., Bosco, D.A., Kern, D. J. Mol. Biol. (2007) [Pubmed]
  7. Long-term outcome for men with androgen independent prostate cancer treated with ketoconazole and hydrocortisone. Scholz, M., Jennrich, R., Strum, S., Brosman, S., Johnson, H., Lam, R. J. Urol. (2005) [Pubmed]
  8. Myc confers androgen-independent prostate cancer cell growth. Bernard, D., Pourtier-Manzanedo, A., Gil, J., Beach, D.H. J. Clin. Invest. (2003) [Pubmed]
  9. Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. Dahut, W.L., Gulley, J.L., Arlen, P.M., Liu, Y., Fedenko, K.M., Steinberg, S.M., Wright, J.J., Parnes, H., Chen, C.C., Jones, E., Parker, C.E., Linehan, W.M., Figg, W.D. J. Clin. Oncol. (2004) [Pubmed]
  10. Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. Beer, T.M., Eilers, K.M., Garzotto, M., Egorin, M.J., Lowe, B.A., Henner, W.D. J. Clin. Oncol. (2003) [Pubmed]
  11. Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer. Oh, W.K., Kantoff, P.W., Weinberg, V., Jones, G., Rini, B.I., Derynck, M.K., Bok, R., Smith, M.R., Bubley, G.J., Rosen, R.T., DiPaola, R.S., Small, E.J. J. Clin. Oncol. (2004) [Pubmed]
  12. Expression of the epidermal growth factor receptor family in prostate carcinoma before and during androgen-independence. Hernes, E., Fosså, S.D., Berner, A., Otnes, B., Nesland, J.M. Br. J. Cancer (2004) [Pubmed]
  13. Pin1 allows for differential Tau dephosphorylation in neuronal cells. Hamdane, M., Dourlen, P., Bretteville, A., Sambo, A.V., Ferreira, S., Ando, K., Kerdraon, O., Bégard, S., Geay, L., Lippens, G., Sergeant, N., Delacourte, A., Maurage, C.A., Galas, M.C., Buée, L. Mol. Cell. Neurosci. (2006) [Pubmed]
  14. Functionally Important Residues in the Peptidyl-prolyl Isomerase Pin1 Revealed by Unigenic Evolution. Behrsin, C.D., Bailey, M.L., Bateman, K.S., Hamilton, K.S., Wahl, L.M., Brandl, C.J., Shilton, B.H., Litchfield, D.W. J. Mol. Biol. (2007) [Pubmed]
  15. Pin1 in Alzheimer's disease. Butterfield, D.A., Abdul, H.M., Opii, W., Newman, S.F., Joshi, G., Ansari, M.A., Sultana, R. J. Neurochem. (2006) [Pubmed]
  16. Proteolytic cleavage of PDZD2 generates a secreted peptide containing two PDZ domains. Yeung, M.L., Tam, T.S., Tsang, A.C., Yao, K.M. EMBO Rep. (2003) [Pubmed]
  17. PAPIN. A novel multiple PSD-95/Dlg-A/ZO-1 protein interacting with neural plakophilin-related armadillo repeat protein/delta-catenin and p0071. Deguchi, M., Iizuka, T., Hata, Y., Nishimura, W., Hirao, K., Yao, I., Kawabe, H., Takai, Y. J. Biol. Chem. (2000) [Pubmed]
  18. Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1. Yu, L., Mohamed, A.J., Vargas, L., Berglöf, A., Finn, G., Lu, K.P., Smith, C.I. J. Biol. Chem. (2006) [Pubmed]
  19. A new parameter for measuring metastatic bone involvement by prostate cancer: the Bone Scan Index. Imbriaco, M., Larson, S.M., Yeung, H.W., Mawlawi, O.R., Erdi, Y., Venkatraman, E.S., Scher, H.I. Clin. Cancer Res. (1998) [Pubmed]
  20. Proteolytic nicking of the acetylcholine receptor. Lindstrom, J., Gullick, W., Conti-Tronconi, B., Ellisman, M. Biochemistry (1980) [Pubmed]
  21. Cell-killing potential of a water-soluble radical initiator. Ameer, G.A., Crumpler, E.T., Langer, R. Int. J. Cancer (2001) [Pubmed]
  22. Localization of p0071-interacting proteins, plakophilin-related armadillo-repeat protein-interacting protein (PAPIN) and ERBIN, in epithelial cells. Ohno, H., Hirabayashi, S., Iizuka, T., Ohnishi, H., Fujita, T., Hata, Y. Oncogene (2002) [Pubmed]
  23. GABAB Receptor Association with the PDZ Scaffold Mupp1 Alters Receptor Stability and Function. Balasubramanian, S., Fam, S.R., Hall, R.A. J. Biol. Chem. (2007) [Pubmed]
  24. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. Bubley, G.J., Carducci, M., Dahut, W., Dawson, N., Daliani, D., Eisenberger, M., Figg, W.D., Freidlin, B., Halabi, S., Hudes, G., Hussain, M., Kaplan, R., Myers, C., Oh, W., Petrylak, D.P., Reed, E., Roth, B., Sartor, O., Scher, H., Simons, J., Sinibaldi, V., Small, E.J., Smith, M.R., Trump, D.L., Wilding, G. J. Clin. Oncol. (1999) [Pubmed]
  25. Multiple cycles of intermittent chemotherapy in metastatic androgen-independent prostate cancer. Beer, T.M., Garzotto, M., Henner, W.D., Eilers, K.M., Wersinger, E.M. Br. J. Cancer (2004) [Pubmed]
  26. A randomized, phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases. Figg, W.D., Liu, Y., Arlen, P., Gulley, J., Steinberg, S.M., Liewehr, D.J., Cox, M.C., Zhai, S., Cremers, S., Parr, A., Yang, X., Chen, C.C., Jones, E., Dahut, W.L. J. Urol. (2005) [Pubmed]
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