Hamid Band, MD,
PhD
Professor
Department of Medicine
Director, Division of Molecular Oncology
Evanston Northwestern Healthcare Research Institute
To contact Dr. Band:
E-mail: h-band@northwestern.edu
Dr. Band's Website
PubMed
Reference Lookup
Research Interests:
Dr. Band’s research laboratory is in the Division of Molecular Oncology
at the Evanston Northwestern Healthcare Research Institute of the Feinberg
School of Medicine, Northwestern University, in Evanston. The major focus
of the laboratory is to define the elements of cancer cell signaling and use
these to develop targeted therapeutics and early diagnostic/prognostic markers
in cancer.
A major direction in the laboratory is to define the role of Cbl-family proteins,
initially identified as proto-oncogene products, as negative regulators of
signals initiated by tyrosine kinase-coupled cell surface receptors. This
work follows directly from their discovery that Cbl is a major and ubiquitous
substrate of a number of protein tyrosine kinases, and the demonstration of
its physical associations with a number of crucial intracellular signal transduction
proteins. Cbl has also emerged as a critical negative regulator of EGF and
PDGF receptor tyrosine kinases, and Cbl-deficient mice exhibit a pronounced
increase in mammary gland branching and hyper-cellularity of other organs.
The targets of Cbl-mediated regulation in lymphocytes include Syk/ZAP70 tyrosine
kinases as well as members of the Src-family kinases. Indeed, Cbl-deficient
mice exhibit increased positive selection of CD4 cells, and Cbl-b-deficient
mice are prone to spontaneous and/or induced autoimmunity and their T cells
become co-stimulation-independent. Elucidation of the biochemical machinery
that mediates the role of Cbl as a negative regulator of receptor tyrosine
kinases is therefore of great interest.
With three known mammalian Cbl family proteins, and the identification of
C. elegans and Drosophila Cbl homologues, Cbl has gained substantial importance
in cell biology as the core member of an evolutionarily conserved family of
proteins involved in tyrosine kinase regulation. The Band laboratory’s
recent work has demonstrated that the evolutionarily conserved N-terminal
transforming region of Cbl provides a tyrosine kinase-binding (TKB) domain
that allows selective recruitment of Cbl to activated tyrosine kinases. Recently,
they have shown that the RING finger domain of Cbl, which is also conserved
through evolution, is essential for tyrosine kinase regulation. Together,
the TKB and RING finger domains define a core region of Cbl family proteins
that recruits the ubiquitin machinery for ubiquitination of activated tyrosine
kinases. Recent work in Dr. Band’s laboratory as well as the work of
other groups now provides strong evidence for Cbl-mediated ubiquitination
as a mechanism to control the level of tyrosine kinase signaling either by
facilitating proteasome-mediated catabolism or targeting activated receptors
to lysosomal degradation.
Our current work addresses the nature of the biochemical and cell biological
machinery involved in tyrosine kinase regulation by Cbl. A major effort is
underway to identify and characterize the endocytic machinery that recognizes
the ubiquitin modification of Cbl-regulated receptors and helps sort these
receptors into lysosomes. The focus of these studies is the mammalian ESCRT-1
(Endosomal Sorting Complex Required for Transport) complex, composed of the
homologues of the yeast vacuolar protein sorting components VPS23, VPS28 and
VPS37, together with its regulator VPS4. These new findings have led to a
new direction in the laboratory to investigate the role of ubiquitin-dependent
traffic of ErbB and PDGF receptors. Given the importance of controlling the
intensity of a tyrosine kinase coupled receptors to ensure an appropriate
level of cellular activity, and the dramatic consequences of aberrant tyrosine
kinase activity, our basic studies carry far-reaching implications for understanding
and possibly manipulating a number of pathological entities. For example,
ErbB2, a major participant in the pathogenesis of breast and other epithelial
cancers, is relatively resistant to Cbl-mediated negative regulation. Therefore,
we have investigated if other ubiquitin ligases could downregulate ErbB2.
These studies have led to the identification of a molecular chaperone-associated
ubiquitin ligase CHIP as a mediator of ErbB2 downregulation upon HSP90 inhibition.
As HSP90 inhibitors are now in clinical development as anticancer agents,
these studies provide a strong translational potential for breast cancer therapy.
In particular, our laboratory is investigating the possibility of combining
CHIP and Cbl ubiquitin ligase pathways for potentiation of anti-ErbB2 therapy.
Activated receptor tyrosine kinases that are not sorted to lysosomes continue to signal intracellularly and are eventually recycled to the cell surface for repeated cycles of signaling. This is a pattern seen with ErbB2 and accounts for its signaling superiority and higher oncogenic potential. Therefore, we are investigating the nature of intracellular signals that emanate from internalized ErbB receptors and the nature of molecular machinery that controls the duration of their intracellular transit and final recycling. These studies focus on the role of Src-family tyrosine kinases, which are known to collaborate with ErbB receptors and on a new family of recycling endocytic proteins with EH domains – the EHD protein family. These basic studies are aimed at understanding a fundamental cellular process and at translating these lessons into clinical practice to develop targeted therapies against cancer and/or to improve current therapeutic regimens.