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insulin tyrosine kinase signaling: such as the tyrosine phosphorylation of insulin
receptor substrate-1/2 (IRS-1/2) or the blocking of the association between p60–70
and the regulatory subunit of phosphatidyl inositol 3-kinase (PI3K): p85, causing an
inhibition of PI3K activity (Sanchez-Margalet 1999 ; Gonzalez-Yanes and Sanchez-
Margalet 2000 ) and consequently all the downstream events, such as the prevention
of the activation of protein kinase B (PKB) and S6. Thus, PST addition in insulin
stimulated adipocytes decreases PKB activity by 15% and 20% compared with
basal activity (Gonzalez-Yanes and Sanchez-Margalet 2001 ).
In this context, PST has been found to block insulin pathway through Ser-
phosphorylation of IR beta subunit and IRS1, generating a separation of the
IR-IRS1-PI3K complex and a downregulation of PKB activity. Thus, a 3–4 fold
raise of Ser phosphorylated IR/IRS1 has been found when PST was used (Gonzalez-
Yanes and Sanchez-Margalet 2000 ).
Furthermore, PKC is the key factor to mediate all PST effects on insulin signal-
ing. Thus, blocking PKC activity has been found to prevent IR/IRS1 Ser phosphory-
lation, and PI3K inhibition in hepatocytes and adipocytes. Finally, It has also been
found that this PKC blocking can reduce other physiological actions of PST, such as
insulin stimulated glucose transport or glycogen synthesis (Gonzalez-Yanes and
Sanchez-Margalet 2000 ).
All these findings confirm the anti-insulin effects of PST, and points to the under-
lying mechanism, which seems to be the PKC mediated Ser-phosphorylation,
impairing the Tyr-phosphorylation in insulin receptor signaling.
4.3 More than One Pancreastatin Receptor?
Various studies showed that PST displays its physiological effects in nM range of
concentration (Gayen et al. 2009 ; O’Connor et al. 2005 ). These findings suggest,
that PST receptor should be a typical one for biologically active peptides. As men-
tioned in previous points, this receptor seems to be a glycoprotein which has
Pertussis Toxin sensitive nature, associated with Gαq/11 proteins (Santos-Alvarez and
Sanchez-Margalet 2000 ; Sanchez-Margalet et al. 2000 ; Gonzalez-Yanes et al. 1999 ,
2001 ; Sanchez- Margalet et al. 1994a, b). These facts strongly suggest that the PST
receptor should be a GPCR. Nevertheless, due to the insufficient amount of protein
purified, it was not possible to finally demonstrate this hypothesis. More recent
studies discovered the interaction between PST and GRP78, a stress response chap-
erone, which regulates the protein half-life in stressful situations. Not only physical
coupling exists between both molecules, moreover, PST has been shown to inhibit
the ATPase activity of GRP78 (Biswas et al. 2014 ). But being GRP78 an intracel-
lular protein, the question would be how is it possible its interaction with PST on the
cell membrane surface. The answer is that a cell surface form of GRP78 exists
(Arap et al. 2004 ; Delpino and Castelli 2002 ). In this line, it may also act as a recep-
tor for several tumor proliferation-related peptides. Moreover, evidence exist about
the GRP78 mediated AKT activation in cell surface, which is downstream pathway
N.E. Evtikhova et al.