Deterministic early endosomal maturations emerge from a stochastic trigger-and-convert mechanism.

Endosomal maturation is critical for robust and timely cargo transport to specific cellular compartments. The most prominent model of early endosomal maturation involves a phosphoinositide-driven gain or loss of specific proteins on individual endosomes, emphasising an autonomous and stochastic description. However, limitations in fast, volumetric imaging long hindered direct whole cell-level measurements of absolute numbers of maturation events.

The mechanisms of class 1A PI3K and Wnt/β-catenin coupled signaling in breast cancer.

The class IA PI3K signaling pathway is activated by growth factor stimulation and regulates a signaling cascade that promotes diverse events including cell growth, proliferation, migration and metabolism. PI3K signaling is one of the most commonly hyperactivated pathways in breast cancer, leading to increased tumor growth and progression. PI3K hyperactivation occurs via a number of genetic and epigenetic mechanisms including mutation or amplification of PIK3CA, the gene encoding the p110α subunit of PI3Kα, as well as via dysregulation of the upstream growth factor receptors or downstream signaling effectors.

The FDA-Approved Drug Pyrvinium Selectively Targets ER Breast Cancer Cells with High INPP4B Expression.

The majority of breast cancers are estrogen receptor-positive (ER), and endocrine therapies that suppress ER signaling are the standard-of-care treatment for this subset. However, up to half of all ER cancers eventually relapse, highlighting a need for improved clinical therapies. The phosphoinositide phosphatase, INPP4B, is overexpressed in almost half of all ER breast cancers, and promotes Wnt/β-catenin signaling, cell proliferation and tumor growth.

Autophagic lysosome reformation in health and disease.

Lysosomes are the primary degradative compartment within cells and there have been significant advances over the past decade toward understanding how lysosome homeostasis is maintained. Lysosome repopulation ensures sustained autophagy function, a fundamental process that protects against disease. During macroautophagy/autophagy, cellular debris is sequestered into phagophores that mature into autophagosomes, which then fuse with lysosomes to generate autolysosomes in which contents are degraded.

Sequential conversion of PtdIns3P to PtdIns(3,5)P via endosome maturation couples nutrient signaling to lysosome reformation and basal autophagy.

Macroautophagy/autophagy occurs basally under nutrient-rich conditions in most mammalian cells, contributing to protein and organelle quality control, and protection against aging and neurodegeneration. During autophagy, lysosomes are heavily utilized via their fusion with autophagosomes and must be repopulated to maintain autophagic degradative capacity. During starvation-induced autophagy, lysosomes are generated via biogenesis under the control of TFEB (transcription factor EB), or by the recycling of autolysosome membranes via autophagic lysosome reformation (ALR).

Endosome maturation links PI3Kα signaling to lysosome repopulation during basal autophagy.

Autophagy depends on the repopulation of lysosomes to degrade intracellular components and recycle nutrients. How cells co-ordinate lysosome repopulation during basal autophagy, which occurs constitutively under nutrient-rich conditions, is unknown. Here, we identify an endosome-dependent phosphoinositide pathway that links PI3Kα signaling to lysosome repopulation during basal autophagy.

A late endosome signaling hub that couples PI3Kα and WNT/β-catenin signaling in breast cancer.

AKT is the central phosphoinositide 3-kinase (PI3K) signaling effector, however, (p110α subunit of PI3Kα)-mutant estrogen receptor-positive (ER) breast cancers exhibit minimal AKT activation and the downstream signaling is poorly characterized. We discovered that a subset of -mutant ER breast cancers exhibit increased inositol polyphosphate 4-phosphatase type II (INPP4B) expression, which promotes late endosome formation and glycogen synthase kinase 3 beta (GSK3β) trafficking, leading to enhanced Wingless-related integration site (WNT)/catenin beta 1 (β-catenin) activation.

The INPP4B paradox: Like PTEN, but different.

Cancer is a complex and heterogeneous disease marked by the dysregulation of cancer driver genes historically classified as oncogenes or tumour suppressors according to their ability to promote or inhibit tumour development and growth, respectively. Certain genes display both oncogenic and tumour suppressor functions depending on the biological context, and as such have been termed dual-role cancer driver genes. However, because of their context-dependent behaviour, the tumourigenic mechanism of many dual-role genes is elusive and remains a significant knowledge gap in our effort to understand and treat cancer.

INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer.

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear.

Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation.

Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. To address this gap, we use mass spectrometry-based chemical proteomics to characterize the global impact of an oncogene on the expressed kinome, and then functionally annotate the regulated kinases. As an example, we identify 63 protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells.

Regulation of PI3K effector signalling in cancer by the phosphoinositide phosphatases.

Class I phosphoinositide 3-kinase (PI3K) generates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)) at the plasma membrane in response to growth factors, activating a signalling cascade that regulates many cellular functions including cell growth, proliferation, survival, migration and metabolism. The PI3K pathway is commonly dysregulated in human cancer, and drives tumorigenesis by promoting aberrant cell growth and transformation. PtdIns(3,4,5) facilitates the activation of many pleckstrin homology (PH) domain-containing proteins including the serine/threonine kinase AKT.