JCB biowrites

ASCB 2013: Signaling knows its place

On Monday afternoon at ASCB 2013, I took in the minisymposium on the Spatial Regulation of Signaling, organized by Johanna Ivaska (University of Turku) and Rajat Rohatgi (Stanford). The session covered a lot of ground, exploring many different signaling events taking place in many different parts of the cell.

Image of a human fibroblast migrating through collagen © 2012 Petrie et al.

Several of the talks discussed pathways involved in cell adhesion. Jonna Alanko (from Ivaska’s lab) described an interesting new way of compartmentalizing the signals from integrin adhesion molecules. Brian Beaty (from John Condeelis’ lab at the Albert Einstein College of Medicine) discussed the role of integrin signaling in the formation of invadopodia, the actin-rich membrane protrusions that drive cancer cell invasion through the extracellular matrix. Beaty, who has previously shown that β1 integrin localizes to invadopodia, described how integrin-binding proteins stimulate actin polymerization in invadopodia. And Matthew Kutys (a member of Ken Yamada’s laboratory at the NIH) discussed how cells migrating through different types of extracellular matrix activate different Rho GTPase pathways  that affect their mode of motility.

Cecile Gauthier-Rouviere (Montpelier) focused on intercellular adhesions, revealing that flotillins 1 and 2 promote the assembly of adherens junctions by stabilizing the presence of cadherin adhesion molecules in plasma membrane microdomains at cell-cell contacts.

Sigrid Nachtergaele (from Rohatgi’s group) described how the oxysterol 20(S)-OHC activates the Hedgehog signaling pathway by binding to the seven-pass transmembrane protein Smoothened. Activated smoothened accumulates in the primary cilium, and this organelle – often described as the cell’s antenna – is a critical location for many other signaling pathways in addition to the Hedgehog pathway. Mutations that disrupt ciliary function cause a group of human diseases – ciliopathies – characterized by a diverse set of symptoms reflecting the variety of tissues and signaling pathways that can be affected. Obesity is a common feature of ciliopathies and Alexander Loktev (working with Peter Jackson at Genentech and at Stanford) described how the BBSome – a group of proteins mutated in the ciliopathy Bardet-Biedl Syndrome – transports the G protein-coupled receptor NPY2R into the cilia of neurons in the hypothalamus. NPY2R and its ligand PYY2-36 suppress the appetite, but mice lacking BBSome components couldn’t localize NPY2R to the primary cilium and couldn’t activate the pathway, leading to increased food intake.

And finally, Art Alberts (from the Van Andel Research Institute in Grand Rapids) discussed the various ways that cells can exchange membrane with one another. Different cell types carry out this exchange in different ways, but it appears to be an almost universal process that allows cells to exchange material and influence each other’s behavior. 

ASCB 2013: The changing shape of organelles

Laissez les bon temps rouler! The 2013 ASCB meeting is well underway here in New Orleans. After a terrific pair of keynote lectures from Elaine Fuchs and Craig Venter on the opening night of the meeting, I attended the minisymposium on Organelle Biogenesis and Dynamics on Sunday afternoon.

I’ve always been fascinated by membrane-bound organelles. I worked on the Golgi apparatus as a PhD student and, back then, most of the field was concerned with trafficking between organelles in the secretory and endocytic pathways. Nowadays, however, there’s a whole lot more going on, and Sunday’s session – organized by Tobias Walther and Luca Scorrano – exemplified the growing awareness of the complex functions and dynamics of cellular organelles.

It’s now clear, for example, that organelles serve as signaling platforms. Two of the talks on Sunday illustrated how the activity of a family of transcription factors is regulated on the surface of lysosomes. Shawn Ferguson (Yale) discussed his recent JCB paper describing how the tumor suppressor Folliculin, which is mutated in Birt-Hogg-Dubé syndrome, promotes the amino acid-dependent activation of mTOR kinase on lysosomes, leading to the sequestration of the transcription factor TFEB in the cytoplasm. (TFEB itself is the master regulator of lysosome and autophagosome biogenesis). As Ferguson told me when I spoke to him in October, hyperactivation of TFEB and related transcription factors in the absence of folliculin may promote tumorigenesis in patients with Birt-Hogg-Dubé syndrome. Meanwhile, Jose Martina (from Rosa Puertollano’s laboratory at the NIH) presented some work following up on his JCB paper from earlier this year demonstrating that Rag GTPases recruit TFEB to lysosomal membranes so that it can be phosphorylated by mTOR.

 

Image of ER (green) and mitochondria (red) © 2010 Friedman et al.

Another  recent development in organelle biology is the growing appreciation for the extent and importance of interorganellar contacts. Many of these contacts involve the endoplasmic reticulum, which forms an extensive tubular network throughout the cytoplasm and therefore contacts many other organelles. Gia Voeltz’s lab at UC Boulder has shown that the ER is closely associated with endosomes, and Ashley Rowland, a grad student in Voeltz’s lab discussed the functional significance of these contacts. Voeltz’s lab has also shown that the ER wraps around mitochondria and marks the sites of mitochondrial fission. Uri Manor (from Jennifer Lippincott-Schwartz’s lab at the NIH) described an interaction between an ER and a mitochondrial protein that may help this process. And Laura Lackner (Northwestern) explained how, in budding yeast, the ER contributes to a cortical tethering complex that helps to position mitochondria and regulate mitochondrial inheritance.

The other two talks in the minisymposium touched on a couple of other interesting aspects of organelle dynamics. Nora Kory (from Tobias Walther’s lab at Yale) discussed what happens to lipid droplet proteins when lipids are mobilized from these storage organelles to provide energy for the cell. And Mark Chan (from Wallace Marshall’s group at UCSF) described how the budding yeast vacuole scales with cell size.

The session was really well attended and there were plenty of enthusiastic questions after every talk. In my opinion, membrane-bound organelles have always been interesting but it seems that’s more true now than ever before.