Signalling of Adrenoceptors: Canonical Pathways and New Paradigms.

The concept of G protein-coupled receptors initially arose from studies of the ß-adrenoceptor, adenylyl cyclase, and cAMP signalling pathway. Since then both canonical G protein-coupled receptor signalling pathways and emerging paradigms in receptor signalling have been defined by experiments focused on adrenoceptors. Here, we discuss the evidence for G protein coupling specificity of the nine adrenoceptor subtypes. We summarise the ability of each of the adrenoceptors to activate proximal signalling mediators including cAMP, calcium, mitogen-activated protein kinases, and protein kinase C pathways. Finally, we highlight the importance of precise spatial and temporal control of adrenoceptor signalling that is controlled by the localisation of receptors at intracellular membranes and in larger protein complexes.

Pathological changes in GPCR signal organisation: Opportunities for targeted therapies for triple negative breast cancer.

Triple negative breast cancer (TNBC) has the poorest prognosis compared to other breast cancer subtypes, due to a historical lack of targeted therapies and high rates of relapse. Greater insight into the components of signalling pathways in TNBC tumour cells has led to the clinical evaluation, and in some cases approval, of targeted therapies. In the last decade, G protein-coupled receptors, such as the ß2-adrenoceptor, have emerged as potential new therapeutic targets. Here, we describe how the ß2-adrenoceptor accelerates TNBC progression in response to stress, and the unique signalling pathway activated by the ß2-adrenoceptor to drive the invasion of an aggressive TNBC tumour cell. We highlight evidence that supports an altered organisation of GPCRs in tumour cells, and suggests that activation of the same GPCR in a different cellular location can control unique cell responses. Finally, we speculate how the relocation of GPCRs to the "wrong" place in tumour cells presents opportunities to develop targeted anti-cancer GPCR drugs with greater efficacy and minimal adverse effects.

Structural analysis of the PTEN:P-Rex2 signaling complex reveals how cancer-associated mutations coordinate to hyperactivate Rac1.

The dual-specificity phosphatase PTEN functions as a tumor suppressor by hydrolyzing PI(3,4,5)P3 to PI(4,5)P2 to inhibit PI3K-AKT signaling and cellular proliferation. P-Rex2 is a guanine nucleotide exchange factor for Rho GTPases and can be activated by Gßγ subunits downstream of G protein-coupled receptor signaling and by PI(3,4,5)P3 downstream of receptor tyrosine kinases. The PTEN:P-Rex2 complex is a commonly mutated signaling node in metastatic cancer. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cellular proliferation. Here, using cross-linking mass spectrometry and functional studies, we gained mechanistic insights into PTEN:P-Rex2 complex assembly and coinhibition. We found that PTEN was anchored to P-Rex2 by interactions between the PDZ-interacting motif in the PTEN C-terminal tail and the second PDZ domain of P-Rex2. This interaction bridged PTEN across the P-Rex2 surface, preventing PI(3,4,5)P3 hydrolysis. Conversely, PTEN both allosterically promoted an autoinhibited conformation of P-Rex2 and blocked its binding to Gßγ. In addition, we observed that the PTEN-deactivating mutations and P-Rex2 truncations combined to drive Rac1 activation to a greater extent than did either single variant alone. These insights enabled us to propose a class of gain-of-function, cancer-associated mutations within the PTEN:P-Rex2 interface that uncouple PTEN from the inhibition of Rac1 signaling.