Mutations in the tumor suppressor gene PTEN (MMAC1/TEP1) are associated with a large number of human cancers and several autosomal-dominant disorders. Mice mutant for PTEN die at early embryonic stages and the mutant embryonic fibroblasts display decreased sensitivity to cell death. Overexpression of PTEN in different mammalian tissue culture cells affects various processes including cell proliferation, cell death and cell migration. We have characterized the Drosophila PTEN gene and present evidence that both inactivation and overexpression of PTEN affect cell size, while overexpression of PTEN also inhibits cell cycle progression at early mitosis and promotes cell death during eye development in a context-dependent manner. Furthermore, we have shown that PTEN acts in the insulin signaling pathway and all signals from the insulin receptor can be antagonized by either Drosophila or human PTEN, suggesting a potential means for alleviating symptoms associated with altered insulin signaling.

Bohni
R.
,
Riesgo-Escovar
J.
,
Oldham
S.
,
Brogiolo
W.
,
Stocker
H.
,
Andruss
B. F.
,
Beckingham
K.
,
Hafen
E.
(
1999
)
Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4.
Cell
97
,
865
875
Brand
A. H.
,
Perrimon
N.
(
1993
)
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.
Development
118
,
401
415
Cairns
P.
,
Okami
K.
,
Halachmi
S.
,
Halachmi
N.
,
Esteller
M.
,
Herman
J. G.
,
Jen
J.
,
Isaacs
W. B.
,
Bova
G. S.
,
Sidransky
D.
(
1997
)
Frequent inactivation of PTEN/MMAC1 in primary prostate cancer.
Cancer Res
57
,
4997
5000
Cantley
L. C.
,
Neel
B. G.
(
1999
)
New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway.
Proc. Natl. Acad. Sci. USA
96
,
4240
4245
Cheney
I. W.
,
Johnson
D. E.
,
Vaillancourt
M. T.
,
Avanzini
J.
,
Morimoto
A.
,
Demers
G. W.
,
Wills
K. N.
,
Shabram
P. W.
,
Bolen
J. B.
,
Tavtigian
S. V.
, et al. 
(
1998
)
Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer.
Cancer Res
58
,
2331
2334
de Nooij
J. C.
,
Hariharan
I. K.
(
1995
)
Uncoupling cell fate determination from patterned cell division in the Drosophila eye [see comments].
Science
270
,
983
985
Denu
J. M.
,
Stuckey
J. A.
,
Saper
M. A.
,
Dixon
J. E.
(
1996
)
Form and function in protein dephosphorylation.
Cell
87
,
361
364
Di Cristofano
A.
,
Pesce
B.
,
Cordon-Cardo
C.
,
Pandolfi
P. P.
(
1998
)
Pten is essential for embryonic development and tumour suppression.
Nat. Genet
19
,
348
355
Furnari
F. B.
,
Huang
H. J.
,
Cavenee
W. K.
(
1998
)
The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1growth arrest in glioma cells.
Cancer Res
58
,
5002
5008
Furnari
F. B.
,
Lin
H.
,
Huang
H. S.
,
Cavenee
W. K.
(
1997
)
Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain.
Proc. Natl. Acad. Sci. USA
94
,
12479
12484
Gil
E. B.
,
Malone Link
E.
,
Liu
L. X.
,
Johnson
C. D.
,
Lees
J. A.
(
1999
)
Regulation of the insulin-like developmental pathway of Caenorhabditis elegans by a homolog of the PTEN tumor suppressor gene.
Proc. Natl. Acad. Sci. USA
96
,
2925
2930
Gu
J.
,
Tamura
M.
,
Pankov
R.
,
Danen
E. H.
,
Takino
T.
,
Matsumoto
K.
,
Yamada
K. M.
(
1999
)
Shc and FAK differentially regulate cell motility and directionality modulated by PTEN.
J. Cell Biol
146
,
389
403
Guldberg
P.
,
thor Straten
P.
,
Birck
A.
,
Ahrenkiel
V.
,
Kirkin
A. F.
,
Zeuthen
J.
(
1997
)
Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma.
Cancer Res
57
,
3660
3663
Halder
G.
,
Callaerts
P.
,
Flister
S.
,
Walldorf
U.
,
Kloter
U.
,
Gehring
W. J.
(
1998
)
Eyeless initiates the expression of both sine oculis and eyes absent during Drosophila compound eye development.
Development
125
,
2181
2191
Hay
B. A.
,
Wolff
T.
,
Rubin
G. M.
(
1994
)
Expression of baculovirus P35 prevents cell death in Drosophila.
Development
120
,
2121
2129
Leevers
S. J.
,
Weinkove
D.
,
MacDougall
L. K.
,
Hafen
E.
,
Waterfield
M. D.
(
1996
)
The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth.
EMBO J
15
,
6584
6594
Li
D. M.
,
Sun
H.
(
1997
)
TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta.
Cancer Res
57
,
2124
2129
Li
D. M.
,
Sun
H.
(
1998
)
PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1cell cycle arrest in human glioblastoma cells.
Proc. Natl. Acad. Sci. USA
95
,
15406
15411
Li
J.
,
Simpson
L.
,
Takahashi
M.
,
Miliaresis
C.
,
Myers
M. P.
,
Tonks
N.
,
Parsons
R.
(
1998
)
The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene.
Cancer Res
58
,
5667
5672
Li
J.
,
Yen
C.
,
Liaw
D.
,
Podsypanina
K.
,
Bose
S.
,
Wang
S. I.
,
Puc
J.
,
Miliaresis
C.
,
Rodgers
L.
,
McCombie
R.
, et al. 
(
1997
)
PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer [see comments].
Science
275
,
1943
1947
Li
L.
,
Ernsting
B. R.
,
Wishart
M. J.
,
Lohse
D. L.
,
Dixon
J. E.
(
1997
)
A family of putative tumor suppressors is structurally and functionally conserved in humans and yeast.
J. Biol. Chem
272
,
29403
29406
Liaw
D.
,
Marsh
D. J.
,
Li
J.
,
Dahia
P. L.
,
Wang
S. I.
,
Zheng
Z.
,
Bose
S.
,
Call
K. M.
,
Tsou
H. C.
,
Peacocke
M.
, et al. 
(
1997
)
Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.
Nat. Genet
16
,
64
67
Liu
W.
,
James
C. D.
,
Frederick
L.
,
Alderete
B. E.
,
Jenkins
R. B.
(
1997
)
PTEN/MMAC1 mutations and EGFR amplification in glioblastomas.
Cancer Res
57
,
5254
5257
Maehama
T.
,
Dixon
J. E.
(
1998
)
The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.
J. Biol. Chem
273
,
13375
13378
Marsh
D. J.
,
Dahia
P. L.
,
Zheng
Z.
,
Liaw
D.
,
Parsons
R.
,
Gorlin
R. J.
,
Eng
C.
(
1997
)
Germline mutations in PTEN are present in Bannayan-Zonana syndrome.
Nat. Genet
16
,
333
334
Mihaylova
V. T.
,
Borland
C. Z.
,
Manjarrez
L.
,
Stern
M. J.
,
Sun
H.
(
1999
)
The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway.
Proc. Natl. Acad. Sci. USA
96
,
7427
7432
Myers
M. P.
,
Pass
I.
,
Batty
I. H.
,
Van der Kaay
J.
,
Stolarov
J. P.
,
Hemmings
B. A.
,
Wigler
M. H.
,
Downes
C. P.
,
Tonks
N. K.
(
1998
)
The lipid phosphatase activity of PTEN is critical for its tumor supressor function.
Proc. Natl. Acad. Sci. USA
95
,
13513
13518
Myers
M. P.
,
Stolarov
J. P.
,
Eng
C.
,
Li
J.
,
Wang
S. I.
,
Wigler
M. H.
,
Parsons
R.
,
Tonks
N. K.
(
1997
)
P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.
Proc. Natl. Acad. Sci. USA
94
,
9052
9057
Myers
M. P.
,
Tonks
N. K.
(
1997
)
PTEN: sometimes taking it off can be better than putting it on.
Am. J. Hum. Genet
61
,
1234
1238
Neufeld
T. P.
,
de la Cruz
A. F.
,
Johnston
L. A.
,
Edgar
B. A.
(
1998
)
Coordination of growth and cell division in the Drosophila wing.
Cell
93
,
1183
1193
Ogg
S.
,
Ruvkun
G.
(
1998
)
The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway.
Mol. Cell
2
,
887
893
Podsypanina
K.
,
Ellenson
L. H.
,
Nemes
A.
,
Gu
J.
,
Tamura
M.
,
Yamada
K. M.
,
Cordon-Cardo
C.
,
Catoretti
G.
,
Fisher
P. E.
,
Parsons
R.
(
1999
)
Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems.
Proc. Natl. Acad. Sci. USA
96
,
1563
1568
Rasheed
B. K.
,
Stenzel
T. T.
,
McLendon
R. E.
,
Parsons
R.
,
Friedman
A. H.
,
Friedman
H. S.
,
Bigner
D. D.
,
Bigner
S. H.
(
1997
)
PTEN gene mutations are seen in high-grade but not in low-grade gliomas.
Cancer Res
57
,
4187
4190
Risinger
J. I.
,
Hayes
A. K.
,
Berchuck
A.
,
Barrett
J. C.
(
1997
)
PTEN/MMAC1 mutations in endometrial cancers.
Cancer Res
57
,
4736
4738
Robinow
S.
,
White
K.
(
1991
)
Characterization and spatial distribution of the ELAV protein during Drosophila melanogaster development.
J. Neurobiol
22
,
443
461
Rouault
J. P.
,
Kuwabara
P. E.
,
Sinilnikova
O. M.
,
Duret
L.
,
Thierry-Mieg
D.
,
Billaud
M.
(
1999
)
Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN.
Curr. Biol
9
,
329
332
Stambolic
V.
,
Suzuki
A.
,
de la Pompa
J. L.
,
Brothers
G. M.
,
Mirtsos
C.
,
Sasaki
T.
,
Ruland
J.
,
Penninger
J. M.
,
Siderovski
D. P.
,
Mak
T. W.
(
1998
)
Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN.
Cell
95
,
29
39
Steck
P. A.
,
Pershouse
M. A.
,
Jasser
S. A.
,
Yung
W. K.
,
Lin
H.
,
Ligon
A. H.
,
Langford
L. A.
,
Baumgard
M. L.
,
Hattier
T.
,
Davis
T.
, et al. 
(
1997
).
Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.
Nat. Genet
15
,
356
362
Sun
H.
,
Lesche
R.
,
Li
D. M.
,
Liliental
J.
,
Zhang
H.
,
Gao
J.
,
Gavrilova
N.
,
Mueller
B.
,
Liu
X.
,
Wu
H.
(
1999
)
PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway.
Proc. Natl. Acad. Sci. USA
96
,
6199
6204
Suzuki
A.
,
de la Pompa
J. L.
,
Stambolic
V.
,
Elia
A. J.
,
Sasaki
T.
,
del Barco Barrantes
I.
,
Ho
A.
,
Wakeham
A.
,
Itie
A.
,
Khoo
W.
, et al. 
(
1998
)
High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice.
Curr. Biol
8
,
1169
1178
Tamura
M.
,
Gu
J.
,
Matsumoto
K.
,
Aota
S.
,
Parsons
R.
,
Yamada
K. M.
(
1998
)
Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN.
Science
280
,
1614
1617
Tao
W.
,
Zhang
S.
,
Turenchalk
G. S.
,
Stewart
R. A.
,
St John
M. A.
,
Chen
W.
,
Xu
T.
(
1999
)
Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity.
Nat. Genet
21
,
177
181
Tashiro
H.
,
Blazes
M. S.
,
Wu
R.
,
Cho
K. R.
,
Bose
S.
,
Wang
S. I.
,
Li
J.
,
Parsons
R.
,
Ellenson
L. H.
(
1997
)
Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies.
Cancer Res
57
,
3935
3940
Theodosiou
N. A.
,
Zhang
S.
,
Wang
W. Y.
,
Xu
T.
(
1998
)
slimb coordinates wg and dpp expression in the dorsal-ventral and anterior-posterior axes during limb development.
Development
125
,
3411
3416
Wang
S. I.
,
Puc
J.
,
Li
J.
,
Bruce
J. N.
,
Cairns
P.
,
Sidransky
D.
,
Parsons
R.
(
1997
)
Somatic mutations of PTEN in glioblastoma multiforme.
Cancer Res
57
,
4183
4186
White
K.
,
Tahaoglu
E.
,
Steller
H.
(
1996
)
Cell killing by the Drosophila gene reaper.
Science
271
,
805
807
Wolff
T.
,
Ready
D. F.
(
1991
)
Cell death in normal and rough eye mutants of Drosophila.
Development
113
,
825
839
Xu
T.
,
Harrison
S. D.
(
1994
)
Mosaic analysis using FLP recombinase.
Meth. Cell Biol
44
,
655
681
Xu
T.
,
Wang
W.
,
Zhang
S.
,
Stewart
R. A.
,
Yu
W.
(
1995
)
Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase.
Development
121
,
1053
1063
This content is only available via PDF.