Biology Reference
In-Depth Information
3.1. Overview of ILPs and insulin signaling
The insulin/insulin-like growth factor (IGF)-like signaling (IIS) pathway is
an evolutionary conserved pathway with roles in tissue growth, develop-
ment, metabolic homeostasis, stress resistance, and longevity (
Broughton
et al., 2005; Clancy et al., 2001; Holzenberger et al., 2003; Ikeya, Galic,
Belawat, Nairz, & Hafen, 2002; Partridge, Alic, Bjedov, & Piper, 2011;
Saltiel & Kahn, 2001
). In
D. melanogaster
, insulin gene expression occurs
in a group of 14 neurosecretory cells located in the brain (
Ikeya et al.,
2002
). The
D. melanogaster
genome encodes seven different insulin-like pep-
tides (ILPs) that are expressed and regulated differentially. Ligand binding to
the
D. melanogaster
Insulin receptor (dInR) triggers autophosphorylation
followed by either direct recruitment of phosphoinositol 3-kinase (PI3K)
to the cell membrane or indirect recruitment through insulin receptor
substrates (IRSs) such as Chico, Lnk, and Dreadlocks (
Teleman, 2010
;
see
Fig. 4.1
). The PI3K is a heterodimer of a catalytic subunit Dp110 and
a regulatory subunit Dp60. Together these catalyze conversion of pho-
sphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to phosphatidylinositol
(1,4,5)-trisphosphate [PtdIns(1,4,5)P3]. A counteracting phosphatase Pten
antagonizes PI3K activity and dephosphorylates PtdIns(1,4,5)P3 and
PtdIns(4,5)P2. Accumulation of PtdIns(1,4,5)P3 activates a series of kinases
such as phosphoinositide-dependent kinase 1 (PDK1) and Akt1/protein
kinase B (PKB), which subsequently phosphorylate the transcription factor
Forkhead Box, Sub-Group O (Foxo), leading to its cytoplasmic retention
and thus inhibiting its transcriptional activity in the nucleus (
Teleman,
2010
). Foxo is a key transcriptional regulator that controls both downstream
target genes responsible for growth as well as upstream feedback targets in
the insulin-signaling pathway (
Junger et al., 2003; Puig, Marr, Ruhf, &
Tjian, 2003
).
The nutrient responsive branch of the IIS pathway controls cellular pro-
tein synthesis via target of rapamycin (Tor). The Tor kinase phosphorylates
S6 kinase and eukaryotic initiation factor 4E binding protein (4EBP) to
stimulate protein translation. Akt1/PKB links the insulin and nutrient sig-
naling branches by phosphorylation of tuberous sclerosis 2 (TSC2) in addi-
tion to Foxo (
Hay & Sonenberg, 2004
). In
D. melanogaster
larvae, the fat
body is the tissue involved in sensing and relaying nutrient availability to
coordinate growth of the whole organism. Low protein levels in the diet
or amino acid deprivation results in inhibition of TOR kinase activity. This
decreased TOR kinase signaling is relayed to other peripheral tissues like
