**5. Regulation of β-cell proliferation by signal pathways from L-PHP to growth hormone activity in pancreatic islet**

L-PHP has been reported to stimulate R1 and dissociate the GPCR complex, activating protein kinase C [29] and mitogen-activated protein kinase (MAPK) [29] in both a PKC-dependent and a PKC-independent manner in the neuronal cell lines [30]. These effects may involve activation of tyrosine kinase, which leads to the activation of Ras and MAPK cascade. The signaling pathways initiating from G-coupled L-PHP receptor in activating MAPK may overlap with the receptor tyrosine kinases activating the Ras-MAPK cascade [31, 32]. There is evidence that L-PHP and EGF have overlapping activities [33] leading to the stimulation of tyrosine phosphorylation of EGF receptors in GH3 cells, a pituitary cell line [34]. L-PHP-induced EGF receptor phosphorylation led to the recruitment of adapter protein Grb2 and Shc in GH3 cells. The hypothesis that L-PHP would activate EGF receptors in β cells through multiple pathways is tested, and data indicated that L-PHP trans-activates EGF receptors through several intraand extracellular pathways, which are distinguished from pituitary-derived cell lines. R1 can initiate multiple signal transduction pathways to activate the epidermal growth factor (EGF) receptor in pancreatic β cells [35]. By initiating R1 G-protein-coupled receptor (GPCR) and dissociated αβγ complex, L-PHP (200nM) activates tyrosine residues at Tyr845, (a known target for Src) and Tyr1068 in the EGF receptor complex in an immortalized mouse β-cell line, βTC-6. Through manipulating the activation of Src, PKC and heparin-binding EGF-like growth factor (HB-EGF) with corresponding individual inhibitors and activators, multiple signal transduction pathways linking L-PHP to EGF receptors in βTC-6 cell lines have been revealed. The pathways include the activation of Src kinase and the release of heparin-binding EGF as a consequence of MMP3 activation. Alternatively, L-PHP inhibited PKC activity by reducing EGF receptor serine/threonine phosphorylation, thereby enhancing tyrosine phosphorylation. L-PHP receptor activation of Src may have a central role in mediating the effects of L-PHP on the EGF receptor (Fig. 3). The activation of the EGF receptor by L-PHP in multiple circum‐ stances may have important implications for pancreatic β cell biology. Since EGF receptor expression has been found to have a high activity during the embryonic developmental period [4, 36], the possibility exists that L-PHP activation of EGF receptors in pancreatic β cells may play a role in β-cell development.

functional β-cells during pancreatic tissue injury, which may be significant for diabetic

Thyrotropin-Releasing Hormone (TRH) a Small Molecule in Pancreas Promotes Insulin Producing Cell Proliferation

http://dx.doi.org/10.5772/57550

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Rat islet cell function can be recovered 90-95% from a pancreatectomy after application of glucagon-like peptide 1(GLP-1) [38]. This β-cell regeneration from damaged rat pancreas has also been mimicked by STZ damaged rat pancreas following administration of L-PHP [39]. However, human islet β-cell regeneration may differ from rat and it may require a totally different microenvironment. In order to initiate human islet β-cell functional recovery from damage or loss, pancreatic stem cells or stem cells from other tissue, such as bone marrow, must be able to in vivo differentiate into multiple types of endocrine cells (αβγ) to reconstitute a new endocrine system in response to glucose challenge. Initiating L-PHP generation *in vivo* or administration from *in vitro* may be a way to approach this goal. Before the application of this peptide, a series of studies must be performed 1) to prove L-PHP can induce stem cells in the pancreatic environment to differentiate into β-cells and 2) L-PHP can induce other islet endocrine cells, such as α and γ cells, to support and regulate β-cell function, even β-cell regeneration. The current evidence from in vivo animal models and in vitro is very promising and encouraging; still multiple steps are needed before L-PHP can be applied in human

This work was partially supported by Roger Williams Hospital Research fund, and NIH Grant Number 1R01DK097380-01A1 from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of General Medical Sciences (NIGMS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views

, Ivor Jackson1

2 Department Research, Center of Stem Cell Research, Roger Williams Hospital Providence,

and LuGuang Luo2\*

therapy.

**7. Future directions**

diabetic therapy.

of the NIH.

**Author details**

John Z.Q . Luo1

Rhode Island, USA

, Souriya Vang2

\*Address all correspondence to: lluo@rwmc.org

1 Brown Alpert Medical School, Rhode Island, USA

, Zhao Ting2

**Acknowledgements**

Fig. (3). The scheme summarized the mechanism of L-PHP (TRH) cross talk with EGF receptor in pancreatic β cells. L-PHP binds to its receptor and dissociates GPCR αβγ complex into α and βγ units. The βγ unit activation of the Src kinase directly results in phosphorylation of EGF receptor Tyr 845. In addition, Src indirectly stimulates Tyr 845 phosphorylation by activation of MMP3 to release heparin-binding EGF. Meanwhile, activation of Src kinase inhibition of PKC results in reducing serine/threonine phosphorylation which blocks off the inhibition of serine/threonine phosphorylation on tyrosine phosphorylation and indirectly activates Tyr 1068 phosphorylation in EGF receptor. LPHP activation of EGF receptor phosphorylation results in the activation of cellular signal pathways such as MAPKs. The activation of Src may have a central role in mediating the effects of L-PHP on the EGF receptor. (R = receptor; \_\_\_\_\_ = activation; ------ = suppression) (From reference #35, with permission). **Figure 3.** The scheme summarized the mechanism of L-PHP cross talk with EGF receptor in pancreatic β cells. L-PHP binds to its receptor and dissociates GPCR αβγ complex into α and βγ units. The βγ unit activation of the Src kinase directly results in phosphorylation of EGF receptor Tyr 845. In addition, Src indirectly stimulates Tyr 845 phosphoryla‐ tion by activation of MMP3 to release heparin-binding EGF. Meanwhile, activation of Src kinase inhibition of PKC re‐ sults in reducing serine/threonine phosphorylation which blocks off the inhibition of serine/threonine phosphorylation on tyrosine phosphorylation and indirectly activates Tyr 1068 phosphorylation in EGF receptor. L-PHP activation of EGF receptor phosphorylation results in the activation of cellular signal pathways such as MAPKs. The activation of Src may have a central role in mediating the effects of L-PHP on the EGF receptor. (R=receptor; \_\_\_\_\_=ac‐ tivation;------=suppression) (From reference #35, with permission)
